Heteroaryl-biphenyl amines for the treatment of pd-l1 diseases

ABSTRACT

Compounds are provided that are useful as immunomodulators. The compounds have the Formula (I) 
     
       
         
         
             
             
         
       
     
     including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 2a , R 2b , R 3 , R 3a , R 4 , R 6 , R 7 , R 8 , A, Z, X 1  and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C § 119(e)to U.S. Provisional application Ser. No. 62/915,771 filed Oct. 16, 2019,the disclosure is incorporated herein by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

Not Applicable

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

Not Applicable

BACKGROUND OF THE DISCLOSURE

Programmed cell death protein-1 (PD-1) is a member of the CD28superfamily that delivers negative signals upon interaction with its twoligands, PD-L1 or PD-L2. PD-1 and its ligands are broadly expressed andexert a wide range of immunoregulatory roles in T cell activation andtolerance. PD-1 and its ligands are involved in attenuating infectiousimmunity and tumor immunity, and facilitating chronic infection andtumor progression.

Modulation of the PD-1 pathway has therapeutic potential in varioushuman diseases (Hyun-Tak Jin et al., Curr Top Microbiol Immunol. (2011);350:17-37). Blockade of the PD-1 pathway has become an attractive targetin cancer therapy. Therapeutic antibodies that block the programmed celldeath protein-1 (PD-1) immune checkpoint pathway prevent T-cell downregulation and promote immune responses against cancer. Several PD-1pathway inhibitors have shown robust activity in various phases ofclinical trials (RD Harvey, Clinical Pharmacology and Therapeutics(2014); 96(2), 214-223).

Agents that block the interaction of PD-L1 with either PD-1 or CD80 aredesired. Some antibodies have been developed and commercialized. A fewpatent applications disclosing non-peptidic small molecules have beenpublished (WO 2015/160641, WO 2015/034820, and WO 2017/066227 andWO2018/009505 from BMS; WO 2015/033299 and WO 2015/033301 from Aurigene;WO 2017/070089, US 2017/0145025, WO 2017/106634, US2017/0174679,WO2017/192961, WO2017/222976, WO2017/205464, WO2017/112730,WO2017/041899 and WO2018/013789 from Incyte, WO2018/006795 fromMaxinovel and WO2018/005374 from us, ChemoCentryx). However there isstill a need for alternative compounds such as small molecules asinhibitors of PD-L1, and which may have advantageous characteristics interm of oral administration, stability, bioavailability, therapeuticindex, and toxicity.

BRIEF SUMMARY OF THE DISCLOSURE

In one aspect, provided herein are compounds having Formula (I):

or a pharmaceutically acceptable salt, prodrug or bioisostere thereof;wherein A, Z, X¹, R^(2a), R^(2b), R³, R^(3a), R⁴, R⁶, R⁷, R⁸, and thesubscript n are as defined herein.

In addition to the compounds provided herein, the present disclosurefurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods associated with preparation and useof such compounds. In some embodiments, the compounds are used intherapeutic methods to treat diseases associated with the PD-1/PD-L1pathway.

BRIEF DESCRIPTION OF THE DRAWINGS

Not Applicable

DETAILED DESCRIPTION OF THE DISCLOSURE Abbreviation and Definitions

The terms “a,” “an,” or “the” as used herein not only include aspectswith one member, but also include aspects with more than one member. Forinstance, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a cell” includes a plurality of such cells andreference to “the agent” includes reference to one or more agents knownto those skilled in the art, and so forth.

The terms “about” and “approximately” shall generally mean an acceptabledegree of error for the quantity measured given the nature or precisionof the measurements. Typical, exemplary degrees of error are within 20percent (%), preferably within 10%, and more preferably within 5% of agiven value or range of values. Alternatively, and particularly inbiological systems, the terms “about” and “approximately” may meanvalues that are within an order of magnitude, preferably within 5-foldand more preferably within 2-fold of a given value. Numerical quantitiesgiven herein are approximate unless stated otherwise, meaning that theterm “about” or “approximately” can be inferred when not expresslystated.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbon group,having the number of carbon atoms designated (i.e. C₁₋₈ means one toeight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group having one or more double bonds. Similarly,the term “alkynyl” refers to an unsaturated alkyl group having one ormore triple bonds. Examples of alkenyl groups include vinyl, 2-propenyl,crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl and3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and3-propynyl, 3-butynyl, and the higher homologs and isomers. The term“cycloalkyl” refers to hydrocarbon rings having the indicated number ofring atoms (e.g., C₃₋₆ cycloalkyl) and being fully saturated or havingno more than one double bond between ring vertices. “Cycloalkyl” is alsomeant to refer to bicyclic and polycyclic hydrocarbon rings such as, forexample, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The bicyclicor polycyclic rings may be fused, bridged, spiro or a combinationthereof. The term “heterocycloalkyl” or “heterocyclyl” refers to acycloalkyl group that contain from one to five heteroatoms selected fromN, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Theheterocycloalkyl may be a monocyclic, a bicyclic or a polycylic ringsystem. The bicyclic or polycyclic rings may be fused, bridged, spiro ora combination thereof. It is understood that the recitation for C₄₋₁₂heterocyclyl, refers to a group having from 4 to 12 ring members whereat least one of the ring members is a heteroatom. Non limiting examplesof heterocycloalkyl groups include pyrrolidine, imidazolidine,pyrazolidine, butyrolactam, valerolactam, imidazolidinone, tetrazolone,hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide,piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone,tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. Aheterocycloalkyl group can be attached to the remainder of the moleculethrough a ring carbon or a heteroatom.

The term “alkylene” by itself or as part of another substituent means adivalent group derived from an alkane, as exemplified by —CH₂CH₂CH₂CH₂—.An alkylene group can be linear or branched. An examples of the latterare —CH₂C(CH₃)₂CH₂—, —CH₂C(CH₃)₂— or —CH(CH₃)CH₂CH₂—. Typically, analkyl (or alkylene) group will have from 1 to 12 carbon atoms, withthose groups having 8 or fewer carbon atoms being preferred in thepresent disclosure. Similarly, “alkenylene” and “alkynylene” refer tothe unsaturated forms of “alkylene” having double or triple bonds,respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon group, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si and S, and wherein the nitrogenand sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. The heteroatom(s) O, N and S may beplaced at any interior position of the heteroalkyl group. The heteroatomSi may be placed at any position of the heteroalkyl group, including theposition at which the alkyl group is attached to the remainder of themolecule. Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the terms“heteroalkenyl” and “heteroalkynyl” by itself or in combination withanother term, means, unless otherwise stated, an alkenyl group oralkynyl group, respectively, that contains the stated number of carbonsand having from one to three heteroatoms selected from the groupconsisting of O, N, Si and S, and wherein the nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) O, N and S may be placed at any interiorposition of the heteroalkyl group.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent group, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— and—S—CH₂—C≡C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like).

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is meant to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “hydroxyalkyl” or “alkyl-OH” refers to an alkyl group, asdefined above, where at least one (and up to three) of the hydrogenatoms is replaced with a hydroxy group. As for the alkyl group,hydroxyalkyl groups can have any suitable number of carbon atoms, suchas C₁₋₆. Exemplary hydroxyalkyl groups include, but are not limited to,hydroxymethyl, hydroxyethyl (where the hydroxy is in the 1- or2-position), hydroxypropyl (where the hydroxy is in the 1-, 2- or3-position), and 2,3-dihydroxypropyl.

The term “C₁₋₃ alkyl-guanidinyl” refers to a C₁₋₃ alkyl group, asdefined above, where at least one of the hydrogen atoms is replaced witha guanidinyl group (—NHC(NH)NH₂).

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to five heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. It is understoodthat the recitation for C₅₋₁₀ heteroaryl, refers to a heteroaryl moietyhaving from 5 to 10 ring members where at least one of the ring membersis a heteroatom. Non-limiting examples of aryl groups include phenyl,naphthyl and biphenyl, while non-limiting examples of heteroaryl groupsinclude pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl,quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl,benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl,thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for eachof the above noted aryl and heteroaryl ring systems are selected fromthe group of acceptable substituents described below.

The term “carbocyclic ring,” “carbocyclic” or “carbocyclyl” refers tocyclic moieties with only carbon atoms as ring vertices. Carbocyclicring moieties are saturated or unsaturated and can be aromatic.Generally, carbocyclic moieties have from 3 to 10 ring members.Carbocyclic moieties with multiple ring structure (e.g. bicyclic) caninclude a cycloalkyl ring fused to an aromatic ring (e.g.1,2,3,4-tetrahydronaphthalene). Thus, carbocyclic rings includecyclopentyl, cyclohexenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl. Theterm “heterocyclic ring” refers to both “heterocycloalkyl” and“heteroaryl” moieties. Thus, heterocyclic rings are saturated orunsaturated and can be aromatic. Generally, heterocyclic rings are 4 to10 ring members and include piperidinyl, tetrazinyl, pyrazolyl andindolyl.

When any of the above terms (e.g., “alkyl,” “aryl” and “heteroaryl”) arereferred to as ‘substituted’ without further notation on thesubstituents, the substituted forms of the indicated group will be asprovided below.

Substituents for the alkyl groups (including those groups often referredto as alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety ofgroups selected from: -halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR'S(O)₂R″, —CN and—NO₂ in a number ranging from zero to (2 m′+1), where m′ is the totalnumber of carbon atoms in such group. R′, R″ and R′″ each independentlyrefer to hydrogen, unsubstituted C₁₋₈ alkyl, unsubstituted heteroalkyl,unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstitutedC₁₋₈ alkyl, C₁₋₈ alkoxy or C₁₋₈ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups. When R′ and R″ are attached to the same nitrogenatom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-,6-, or 7-membered ring. For example, —NR′R″ is meant to include1-pyrrolidinyl and 4-morpholinyl. The term “acyl” as used by itself oras part of another group refers to an alkyl group wherein twosubstitutents on the carbon that is closest to the point of attachmentfor the group is replaced with the substitutent ═O (e.g., —C(O)CH₃,—C(O)CH₂CH₂OR′ and the like).

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR'S(O)₂R″, —N₃, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, unsubstituted aryl and heteroaryl,(unsubstituted aryl)-C₁₋₄ alkyl, and unsubstituted aryloxy-C₁₋₄ alkyl.Other suitable substituents include each of the above aryl substituentsattached to a ring atom by an alkylene tether of from 1-4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The disclosure herein further relates to prodrugs and bioisosteresthereof. Suitable bioisosteres, for example, will include carboxylatereplacements (phosphonic acids, phosphinic acids, sulfonic acids,sulfinic acids, and acidic heterocyclic groups such as tetrazoles).Suitable prodrugs will include those conventional groups known tohydrolyze and/or oxidize under physiological conditions to provide acompound of Formula I.

The terms “patient” and “subject” include primates (especially humans),domesticated companion animals (such as dogs, cats, horses, and thelike) and livestock (such as cattle, pigs, sheep, and the like).

As used herein, the term “treating” or “treatment” encompasses bothdisease-modifying treatment and symptomatic treatment, either of whichmay be prophylactic (i.e., before the onset of symptoms, in order toprevent, delay or reduce the severity of symptoms) or therapeutic (i.e.,after the onset of symptoms, in order to reduce the severity and/orduration of symptoms).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occuring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentdisclosure contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present disclosure.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and are intendedto be encompassed within the scope of the present disclosure.

Certain compounds of the present disclosure may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated by the present disclosure and areintended to be within the scope of the present disclosure.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. When a stereochemical depiction is shown, it is meantto refer to the compound in which one of the isomers is present andsubstantially free of the other isomer. ‘Substantially free of’ anotherisomer indicates at least an 80/20 ratio of the two isomers, morepreferably 90/10, or 95/5 or more. In some embodiments, one of theisomers will be present in an amount of at least 99%.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areintended to be encompassed within the scope of the present disclosure.For example, the compounds may be prepared such that any number ofhydrogen atoms are replaced with a deuterium (²H) isotope. The compoundsof the present disclosure may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. Unnatural proportions of an isotope may be defined as rangingfrom the amount found in nature to an amount consisting of 100% of theatom in question. For example, the compounds may incorporate radioactiveisotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C), or non-radioactive isotopes, such as deuterium (²H) orcarbon-13 (¹³C). Such isotopic variations can provide additionalutilities to those described elsewhere within this application. Forinstance, isotopic variants of the compounds of the disclosure may findadditional utility, including but not limited to, as diagnostic and/orimaging reagents, or as cytotoxic/radiotoxic therapeutic agents.Additionally, isotopic variants of the compounds of the disclosure canhave altered pharmacokinetic and pharmacodynamic characteristics whichcan contribute to enhanced safety, tolerability or efficacy duringtreatment. All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are intended to be encompassedwithin the scope of the present disclosure.

Compounds

In one aspect, the present disclosure provides compounds having formula(I):

-   or a pharmaceutically acceptable salt, prodrug or bioisostere    thereof, wherein:-   A is a 5- to 10-membered heteroaryl group which is unsubstituted or    substituted with from one to five members independently selected    from the group consisting of halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl,    C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, OH, and CN;-   X¹ is C₁₋₃ alkylene, which is unsubstituted or substituted with one    or two members independently selected from the group consisting of    C₁₋₂ alkyl and CO₂H;-   R^(2a) and R^(2b) are each independently selected from the group    consisting of H, C₁₋₈ alkyl, C₁₋₈ haloalkyl, —Y, —X²—CO₂R^(a),    —X²—OR^(a), —X²—NR^(a)R^(b), —X²—C(O)NR^(a)R^(b), —X²—SO₂R^(a),    —X²—SO₂NR^(a)R^(b), —X²—SO₃R^(a) and —X²—Y wherein each X² is C₁₋₆    alkylene and any C₁₋₈ alkyl or C₁₋₆ alkylene, is unsubstituted or    substituted with one or two members independently selected from the    group consisting of OH, SO₂NH₂, C(O)NH₂, C(O)NHOH, PO₃H₂,    CO₂C₁₋₈alkyl and CO₂H, and each Y is selected from the group    consisting of C₃₋₆ cycloalkyl, C₄₋₈ heterocyclyl and 5- to    6-membered heteroaryl, each of which is unsubstituted or substituted    with one to four substituents independently selected from the group    consisting of oxo, OH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄    hydroxyalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ hydroxyalkoxy,    SO₂NH₂, C(O)NH₂, —C(O)NHOH, PO₃H₂, CO₂C₁₋₈alkyl, SO₃H and CO₂H;-   or R^(2a) and R^(2b) are combined to form a 4- to 9-membered ring or    spirocyclic ring, having from zero to two additional heteroatom ring    vertices selected from O, N and S;    -   wherein the ring formed by combining R^(2a) and R^(2b), is        unsubstituted or substituted with 1 to 4 substituents        independently selected from the group consisting of oxo, C₁₋₈        alkyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl, —X³—CO₂R^(a),        —X³—OR^(a), —X³—NR^(a)R^(b), —X³—C(O)NR^(a)R^(b), —X³—SO₂R^(a),        —X³—SO₂NR^(a)R^(b), and —X³—SO₃R^(a); wherein X³ is a bond or        C₁₋₆ alkylene;-   R³ and R⁴ are each independently selected from the group consisting    of H, F, Cl, CN, CH₃, OCH₃, CH₂CH₃ and CF₃;-   the subscript n is 0, 1, 2 or 3;-   each R^(3a) is independently selected from the group consisting of    H, F, Cl, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy,    C₂₋₃ alkenyl and CN;-   R⁶, R⁷ and R⁸ are each independently selected from the group    consisting of H, F, Cl, CN, CH₃, OCH₃, CH₂CH₃ and CF₃;-   Z is a fused bicyclic heteroaryl ring, unsubstituted or substituted    with one to three R^(c);-   each R^(a) is independently selected from the group consisting of H,    C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆    alkylene-CO₂H, and C₁₋₆alkylene-SO₃H;-   each R^(b) is independently selected from the group consisting of H,    C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆    alkylene-CO₂H, and C₁₋₆ alkylene-SO₃H, each of which is    unsubstituted or substituted with one or two members independently    selected from OH, SO₂NH₂, C(O)NH₂, C(O)NHOH, PO₃H₂, CO₂C₁₋₈ alkyl    and CO₂H;-   and R^(a) and R^(b), when attached to the same nitrogen atom, are    optionally combined to form a 4- to 8-membered ring or spirocyclic    ring, which is unsubstituted or substituted with halogen, OH,    SO₂NH₂, C(O)NH₂, C(O)NHOH, PO₃H₂, CO₂C₁₋₈ alkyl or —CO₂H;-   each R^(c) is independently selected from the group consisting of H,    halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —Y¹, —X⁴—CO₂R^(a),    —O—X⁴—CO₂R^(a), —X⁴—OR^(a), —X⁴—NR^(a)R^(b), —X⁴—C(O)NR^(a)R^(b),    —O—X⁴—C(O)NR^(a)R^(b), —X⁴—SO₂R^(a), —X⁴—SO₂NR^(a)R^(b),    —X⁴—SO₃R^(a), and —N(R^(a))—X⁴—CO₂R^(a), wherein each X⁴ is a bond    or C₁₋₆ alkylene, and each Y¹ is selected from the group consisting    of C₃₋₆ cycloalkyl and C₄₋₈ heterocyclyl; and optionally two R^(c)    on adjacent ring vertices are combined to form a fused 5- or    6-membered heterocyclic ring.

In some embodiments, the present disclosure provides compounds ofFormula (I) represented by Formula (Ia):

wherein the groups R^(2a), R^(2b), R³, R⁴, A, X¹ and Z have the meaningsprovided for Formula (I).

In some embodiments, the present disclosure provides compounds ofFormula (I) represented by Formula (Ib):

wherein the groups R^(2a), R^(2b), R³, R⁴, A and Z have the meaningsprovided for Formula (I).

In some selected embodiments, the compounds of Formulae (I), (Ia), or(Ib), are those compounds wherein Z is a fused bicyclic heteroaryl ringhaving a formula selected from the group consisting of:

In some selected embodiments, the compounds of Formulae (I), (Ia), or(Ib), are those compounds wherein Z is a monocyclic 5- or 6-memberedheteroaryl ring, optionally substituted with one to three R^(c); andsaid heterocyclic ring is selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.

In some embodiments, the A group is unsubstituted or substituted withone or two members independently selected from the group consisting ofCF₃, OH, Et, CN, OCH₃ and F. In some embodiments, the A group isunsubstituted or substituted with one or two members independentlyselected from the group consisting of OCH₃ and F.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein the group A is a 5- or 6-membered heteroaryl group and isunsubstituted or substituted with one or two members independentlyselected from halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, OH, andCN. In selected embodiments, including any of those noted above withrespect to the compounds of Formulae (I), (Ia), or (Ib), furtherembodiments are those wherein the group A is a 5- or 6-memberedheteroaryl group and is unsubstituted or substituted with one or twomembers independently selected from halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl,C₁₋₃ alkoxy, and CN. In selected embodiments, including any of thosenoted above with respect to the compounds of Formulae (I), (Ia), or(Ib), further embodiments are those wherein the group A is a 5- or6-membered heteroaryl group and is unsubstituted or substituted with oneor two members independently selected from OCH₃ and F.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein the group A is a 6-membered heteroaryl group which isunsubstituted or substituted with from one to three membersindependently selected from the group consisting of halogen, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, OH, and CN. In selected embodiments,including any of those noted above with respect to the compounds ofFormulae (I), (Ia), or (Ib), further embodiments are those wherein thegroup A is a 6-membered heteroaryl group which is unsubstituted orsubstituted with from one to three members independently selected fromthe group consisting of halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃alkoxy, and CN.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein the group A is selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl,each of which is unsubstituted or substituted with one or two membersindependently selected from the group consisting of halogen, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, OH, and CN. In selectedembodiments, including any of those noted above with respect to thecompounds of Formulae (I), (Ia), or (Ib), further embodiments are thosewherein the group A is selected from the group consisting of pyridinyl,pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl, each ofwhich is unsubstituted or substituted with one or two membersindependently selected from the group consisting of halogen, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, and CN.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein the group A is a 6-membered heteroaryl group selected fromthe group consisting of pyridine, pyrimidine, pyrazine and1,2,4-triazine, each of which is unsubstituted or substituted with oneor two members independently selected from the group consisting of CF₃,OH, Et, CN, OCH₃ and F. In selected embodiments, including any of thosenoted above with respect to the compounds of Formulae (I), (Ia), or(Ib), further embodiments are those wherein the group A is a 6-memberedheteroaryl group selected from the group consisting of pyridine,pyrimidine, pyrazine and 1,2,4-triazine, each of which is unsubstitutedor substituted with one or two members independently selected from thegroup consisting of OCH₃ and F

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein R² and R^(2b) are each H.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein R² and R^(2b) are combined to form a 4- to 9-membered ringor spirocyclic ring, optionally having one or two additional ringvertices selected from O, N or S; wherein said ring or spirocyclic ringis substituted with 0 to 4 substituents independently selected from thegroup consisting of oxo, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl,—X²—C(O)₂R^(a), —X²—OR^(a), —X²—NR^(a)R^(b), —X²—CONR^(a)R^(b),—X²—SO₂R^(a), —X²—SO₂NR^(a)R^(b), and —X²—SO₃R^(a); wherein X² is a bondor C₁₋₆ alkylene.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein N(R^(2a))(R^(2b)) is selected from the group consistingof:

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein N(R^(2a))(R^(2b)) is selected from the group consistingof:

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein N(R^(2a))(R^(2b)) is selected from the group consistingof:

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein R^(2a) is H or C₁₋₈ alkyl; and R^(2b) is —Y or —X²—Y.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein R^(2a) is H or C₁₋₈ alkyl; R^(2b) is —Y or —X²—Y; and Y isselected from the group consisting of C₃₋₆ cycloalkyl and C₄₋₈heterocyclyl, each of which is optionally further substituted with oneto four substituents independently selected from the group consisting ofoxo, OH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, C₁₋₄ hydroxyalkoxy, SO₂NH₂, C(O)NH₂, C(O)NHOH, PO₃H₂,—C(O)₂C₁₋₈ alkyl, and —CO₂H.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein R³ and R⁴ are are each independently selected from thegroup consisting of F, Cl, CN, CH₃, OCH₃, CH₂CH₃ and CF₃. n selectedembodiments, including any of those noted above with respect to thecompounds of Formulae (I), (Ia), or (Ib), further embodiments are thosewherein R³ and R⁴ are are each independently selected from the groupconsisting of Cl, CN, CH₃, and CF₃.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein Z is a 5- or 6-membered non-aromatic heterocyclic ring,optionally substituted with one or two oxo groups and optionallysubstituted with R^(a) and/or R^(b).

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein Z is a monocyclic 5- or 6-membered heteroaryl ring,optionally substituted with one to three R^(c).

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (Ia), or (Ib), further embodiments arethose wherein Z is a 5- or 6-membered non-aromatic heterocyclic ring,optionally substituted with one or two oxo groups and optionallysubstituted with R^(a) and/or R^(b).

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (Ia), or (Ib), further embodiments arethose wherein Z is a monocyclic 5- or 6-membered heteroaryl ring,optionally substituted with one to three R^(c).

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein Z is a 5- or 6-membered non-aromatic heterocyclic ring,optionally substituted with one or two oxo groups and optionallysubstituted with R^(a) and/or R^(b); and said non-aromatic heterocyclicring is selected from the group consisting of piperidinyl, morpholinyl,tetrahydropyranyl, and tetrahydrofuranyl.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein Z is a monocyclic 5- or 6-membered heteroaryl ring,optionally substituted with one to three R^(c); and said heterocyclicring is selected from the group consisting of pyridinyl, pyrimidinyl,pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein the compound is selected from Table 1.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein the compound is selected from Table 1, having ++ or +++activity.

In selected embodiments, including any of those noted above with respectto the compounds of Formulae (I), (Ia), or (Ib), further embodiments arethose wherein the compound is selected from Table 1, having +++activity.

In addition to the compounds provided above, pharmaceutically acceptablesalts of those compounds are also provided. In some embodiments, thepharmaceutically acceptable salts are selected from ammonium, calcium,magnesium, potassium, sodium, zinc, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, hydrochloric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, acetic, propionic,isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, arginate, glucuronic acid and galactunoric acids. Insome embodiments, the pharmaceutically acceptable salts are selectedfrom ammonium, calcium, magnesium, potassium, sodium, hydrochloric,carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, acetic, propionic, isobutyric, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, arginate, glucuronicacid and galactunoric acids. In some embodiments, the pharmaceuticallyacceptable salts are sodium or hydrochloric.

In addition to salt forms, the present disclosure provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Additionally, prodrugs can be converted to the compounds ofthe present disclosure by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present disclosure when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

An ester may be used as a prodrug for the corresponding carboxylic acid.A C₁₋₁₀ alkyl ester or a C₁₋₁₀ haloalkyl ester may be used as a prodrugfor the corresponding carboxylic acid. The following esters may be used:tert-butyl ester, methyl ester, ethyl ester, isopropyl ester.

Methods of Preparation

In addition to the methods described in the Examples below, generalmethods for the preparation of compounds of Formula (I) are provided inSchemes 1 and 2.

Scheme 1 illustrates a general method for the preparation of compoundshaving Formula (I). In the above reaction scheme, A is a six-memberednitrogen containing heteroaryl ring (e.g., pyridyl, pyrimidinyl), X¹ isCH₂, and R^(s) represents one or more substituents on the heteroarylring.

Suzuki-type coupling of (a) with (b) in the presence of a catalyst thenprovides the biphenyl compound (c). A Z group from reagent (d) is addedto the exocylic amine of compound (c) in a substitution reaction to formcompound (e). Compound (e) can then be converted a boronate compound(f), followed by a second Suzuki-type coupling (with a halo-heteroarylcompound (g)) to afford the triaryl aldehyde compound (h). Reductiveamination of the aldehyde with HNR^(2a)R^(2b) can then provide compoundsof Formula (Ia).

Alternatively, a second Suzuki-type coupling of compound (c) in thepresence of compound (g′) and a catalyst provides triaryl aldehydecompound (h), which can be used in reductive amination, as describedabove, to provide compounds of Formula (Ia).

In another Suzuki-coupling based approach, the exocylic amine ofcompound (a) is first substituted with reagent (d) to afford compound(j). Suzuki-type coupling of (j) with (k) in the presence of a catalystprovides compound (h). Triaryl aldehyde compound (h) can be used inreductive amination as described in Scheme I to provide compounds ofFormula (Ia).

Pharmaceutical Compositions

In addition to the compounds provided herein, compositions of thosecompounds will typically contain a pharmaceutical carrier or diluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In another embodiment, a pharmaceutical composition comprising acompound of the present disclosure including a compound of Formulae (I),(Ia), or (Ib), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient, is provided.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutic agents. In some embodiments, the oneor more additional therapeutic agent is selected from the groupconsisting of an antimicrobial agent, an antiviral agent, a cytotoxicagent, a gene expression modulatory agent, a chemotherapeutic agent, ananti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent,an anti-hormonal agent, an anti-fibrotic agent, radiotherapy, aradiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent. In some embodiments, the one or moreadditional therapeutic agent is an antagonist of a chemokine and/orchemoattractant receptor, which includes but is not limited to, CCR1,CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12,CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C₃aR, and/or C₅aR.Chemokine and/or chemoattractant receptor antagonists are known in theart and described in, for example, WO2007/002667, WO2007/002293,WO/2003/105853, WO/2007/022257, WO/2007/059108, WO/2007/044804,WO2007/115232, WO2007/115231, WO2008/147815, WO2010/030815,WO2010/075257, WO2011/163640, WO2010/054006, WO2010/051561,WO2011/035332, WO2013/082490, WO2013/082429, WO2014/085490,WO2014/100735, WO2014/089495, WO2015/084842, WO2016/187393,WO2017/127409, WO 2017/087607, WO2017/087610, WO2017/176620,WO2018/222598, W2018/222601, W2013/130811, WO2006/076644, WO2008/008431,W2009/038847, W2008/008375, W2008/008374, WO2008/010934, WO2009/009740,WO2005/112925, WO2005/112916, WO2005/113513, WO2004/085384,WO2004/046092. Chemokine and/or chemoattractant receptor antagonistsalso include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664,CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430,CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022and/or CCX3384.

The pharmaceutical compositions for the administration of the compoundsof this disclosure may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacyand drug delivery. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self-emulsifications as described in U.S. PatentApplication 2002-0012680, hard or soft capsules, syrups, elixirs,solutions, buccal patch, oral gel, chewing gum, chewable tablets,effervescent powder and effervescent tablets. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents, antioxidants andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated,enterically or otherwise, by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate may beemployed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to formosmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, polyethyleneglycol (PEG) of various average sizes (e.g., PEG400, PEG4000) andcertain surfactants such as cremophor or solutol, or as soft gelatincapsules wherein the active ingredient is mixed with water or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such as mono- ordi-glycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present disclosure may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols. Additionally, the compounds can be administeredvia ocular delivery by means of solutions or ointments. Still further,transdermal delivery of the subject compounds can be accomplished bymeans of iontophoretic patches and the like. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present disclosure are employed. As used herein,topical application is also meant to include the use of mouth washes andgargles.

The compounds of this disclosure may also be coupled with a carrier thatis a suitable polymer for targetable drug carriers. Such polymers caninclude polyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thedisclosure may be coupled to a carrier that is a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like. In one embodiment ofthe disclosure, the compound of the disclosure is coupled to a polymeror semipermeable polymer matrix that is formed as a stent or stent-graftdevice.

Methods of Treating Diseases and Disorders

The compounds of the disclosure may be used as immunomodulators. Thecompounds of the disclosure may be used as agonists, antagonists,partial agonists, inverse agonists, inhibitors of PD-1 and/or PD-L1 in avariety of contexts, both in vitro and in vivo. In some embodiments, thecompounds of the disclosure may be used as inhibitors of the PD-1/PD-L1protein protein interaction. In some embodiments, the compounds of thedisclosure may be used as inhibitors of PD-L1. In some embodiments, thecompounds of the disclosure may be used as inhibitors of the CD80/PD-L1protein protein interaction. In some embodiments, the compounds of thedisclosure may be used to inhibit the interaction between PD-1 and PD-L1and/or PD-1 and CD80 and/or PD-1 and PD-L2 in vitro or in vivo. In someembodiments, the compounds of the disclosure may be used to inhibitVISTA and/or TIM-3. In some embodiments, the compounds of the disclosuremay be inhibitors of the PD-1/PD-L1 protein protein interaction andinhibitors of VISTA and/or TIM-3. In some embodiments, in addition tobeing inhibitors of the PD-1/PD-L1 protein protein interaction, thecompounds of the disclosure may be inhibitors of CTLA-4 and/or BTLAand/or LAG-3 and/or KLRG-1 and/or 2B4 and/or CD160 and/or HVEM and/orCD48 and/or E-cadherin and/or MHC-II and/or galectin-9 and/or CD86and/or PD-L2 and/or VISTA and/or TIM-3 and/or CD80.

The compounds of the disclosure may be contacted with the receptor theyinteract with, in aqueous solution and under conditions otherwisesuitable for binding of the ligand to the receptor. The receptor may bepresent in suspension (e.g., in an isolated membrane or cellpreparation), in a cultured or isolated cell, or in a tissue or organ.

Preferably, the amount of the compounds of the disclosure contacted withthe receptor should be sufficient to inhibit the PD-1/PD-L1 binding invitro as measured, for example, using an ELISA. The receptor may bepresent in solution or suspension, in a cultured or isolated cellpreparation or within a patient.

In some embodiments, the compounds of the present disclosure are usefulfor restoring and augmenting T cell activation. In some embodiments, thecompounds of the present disclosure are useful for enhancing an immuneresponse in a patient. In some embodiments, the compounds of the presentdisclosure are useful for treating, preventing, or slowing theprogression of diseases or disorders in a variety of therapeutic areas,such as cancer and infectious diseases.

In some embodiments, the compounds of the present disclosure can be usedfor treating patients suffering from conditions that are responsive toPD-1/PD-L1 protein protein interaction modulation.

In some embodiments, a method of modulating an immune response mediatedby the PD-1 signaling pathway in a subject, comprising administering tothe subject a therapeutically effective amount of a compound of thepresent disclosure including a compound of Formulae (I), (Ia), or (Ib),or a pharmaceutically acceptable salt thereof or a compositioncomprising a compound of Formulae (I), (Ia), or (Ib), or apharmaceutically acceptable salt thereof, is provided.

In some embodiments, a method of enhancing, stimulating, modulatingand/or increasing the immune response in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure including a compound ofFormulae (I), (Ia), or (Ib), or a pharmaceutically acceptable saltthereof or a composition of a compound of the present disclosureincluding a compound of Formula (I), (Ia), or (Ib), or apharmaceutically acceptable salt thereof, is provided.

In some embodiments, a method of inhibiting growth, proliferation, ormetastasis of cancer cells in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of the present disclosure including a compound of Formula (I),(Ia), or (Ib), or a pharmaceutically acceptable salt thereof or acomposition of a compound of the present disclosure including a compoundof Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable saltthereof, is provided.

In some embodiments, a method of treating a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure including a compound ofFormulae (I), (Ia), or (Ib), or a pharmaceutically acceptable saltthereof or a composition of a compound of the present disclosureincluding a compound of Formulae (I), (Ia), or (Ib), or apharmaceutically acceptable salt thereof, is provided.

In some embodiments, the subject suffers from a disease or disorderselected from the group consisting of an infectious disease, a bacterialinfectious disease, a viral infectious disease a fungal infectiousdisease, a solid tumor, a hematological malignancy, an immune disorder,an inflammatory disease, and cancer. In some embodiments, the disease ordisorder is selected from the group consisting of melanoma,glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma,lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma,diffuse large B-cell lymphoma, primary mediastinal large B-celllymphoma, prostate cancer, castration-resistant prostate cancer, chronicmyelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma,synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of softtissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymusneoplasm, cancer of the thyroid gland, cancer of the parathyroid gland,uterine cancer, cancer of the adrenal gland, liver infection, Merkelcell carcinoma, nerve tumor, follicle center lymphoma, colon cancer,Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acuteleukemias including acute myeloid leukemia, chronic myeloid leukemia,acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiplemyeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocularmalignant melanoma, renal cell carcinoma, small-cell lung cancer, lungcancer, mesothelioma, breast cancer, squamous non-small cell lung cancer(SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastriccancer, hepatocellular carcinoma, pancreatic carcinoma, pancreaticcancer, Pancreatic ductal adenocarcinoma, squamous cell carcinoma of thehead and neck, cancer of the head or neck, gastrointestinal tract,stomach cancer, HIV, Hepatitis A, Hepatitis B, Hepatitis C, hepatitis D,herpes viruses, papillomaviruses, influenza, bone cancer, skin cancer,rectal cancer, cancer of the anal region, testicular cancer, carcinomaof the fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the urethra, cancer of the penis, cancer of thebladder, cancer of the kidney, cancer of the ureter, carcinoma of therenal pelvis, neoplasm of the central nervous system (CNS), tumorangiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma,epidermoid cancer, abestosis, carcinoma, adenocarcinoma, papillarycarcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cellcarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma,embryonal carcinoma, wilm's tumor, pleomorphic adenoma, liver cellpapilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma,leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma,lipoma and fibroma.

In some embodiments, a therapeutically effective amount of one or moreadditional therapeutic agents is further administered to the subject. Insome embodiments, the one or more additional therapeutic agents isselected from the group consisting of an antimicrobial agent, anantiviral agent, a cytotoxic agent, a gene expression modulatory agent,a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenicagent, an immunotherapeutic agent, an anti-hormonal agent, ananti-fibrotic agent, radiotherapy, a radiotherapeutic agent, ananti-neoplastic agent, and an anti-proliferation agent. In someembodiments, the one or more additional therapeutic agent is anantagonist of a chemokine and/or chemoattractant receptor, whichincludes but is not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6,CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4,CXCR5, CXCR6, CXCR7, C3aR, and/or C5aR. Chemokine and/or chemoattractantreceptor antagonists are known in the art and described in, for example,WO2007/002667, WO2007/002293, WO/2003/105853, WO/2007/022257,WO/2007/059108, WO/2007/044804, WO2007/115232, WO2007/115231,WO2008/147815, WO2010/030815, WO2010/075257, WO2011/163640,WO2010/054006, WO2010/051561, WO2011/035332, WO2013/082490,WO2013/082429, WO2014/085490, WO2014/100735, WO2014/089495,WO2015/084842, WO2016/187393, WO2017/127409, WO 2017/087607,WO2017/087610, WO2017/176620, WO2018/222598, W2018/222601, W2013/130811,WO2006/076644, WO2008/008431, W2009/038847, W2008/008375, W2008/008374,WO2008/010934, WO2009/009740, WO2005/112925, WO2005/112916,WO2005/113513, WO2004/085384, WO2004/046092. Chemokine and/orchemoattractant receptor antagonists also include CCX354, CCX9588,CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650,CCX832, CCX168, CCX168-M1, CCX3022 and/or CCX3384.

In some embodiments, the compounds of the present disclosure may be usedto inhibit an infectious disease. The infectious disease includes but isnot limited to HIV, Influenza, Herpes, Giardia, Malaria, Leishmania, thepathogenic infection by the virus Hepatitis (A, B, and C), herpes virus(e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein Barr virus),adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus,coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus,rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus,HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus,rabies virus, JC virus and arboviral encephalitis virus, pathogenicinfection by the bacteria chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,klebsiella, proteus, serratia, pseudomonas, E. coli, legionella,diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax,plague, leptospirosis, and Lyme's disease bacteria, pathogenic infectionby the fungi Candida (albicans, krusei, glabrata, tropicalis, etc.),Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), GenusMucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomycesdermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis andHistoplasma capsulatum, and pathogenic infection by the parasitesEntamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoebasp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosomacruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylusbrasiliensis.

In some embodiments, the compounds of the present disclosure may be usedto inhibit HIV infection, delay AIDS progression, deplete HIV viralreservoir or decrease the severity of symptoms or HIV infection andAIDS.

The compounds of the present disclosure may be used for the treatment ofcancers and precancerous conditions in a subject.

Treatment methods provided herein include, in general, administration toa patient an effective amount of one or more compounds provided herein.Suitable patients include those patients suffering from or susceptibleto (i.e., prophylactic treatment) a disorder or disease identifiedherein. Typical patients for treatment as described herein includemammals, particularly primates, especially humans. Other suitablepatients include domesticated companion animals such as a dog, cat,horse, and the like, or a livestock animal such as cattle, pig, sheepand the like.

In general, treatment methods provided herein comprise administering toa patient an effective amount of a compound one or more compoundsprovided herein. In a preferred embodiment, the compound(s) of thedisclosure are preferably administered to a patient (e.g., a human)intravenously, orally or topically. The effective amount may be anamount sufficient to modulate the PD-1/PD-L1 interaction and/or anamount sufficient to reduce or alleviate the symptoms presented by thepatient. Preferably, the amount administered is sufficient to yield aplasma concentration of the compound (or its active metabolite, if thecompound is a pro-drug) high enough to sufficiently modulate thePD-1/PD-L1 interaction. Treatment regimens may vary depending on thecompound used and the particular condition to be treated; for treatmentof most disorders, a frequency of administration of 4 times daily orless is preferred. In general, a dosage regimen of 2 times daily is morepreferred, with once a day dosing particularly preferred. It will beunderstood, however, that the specific dose level and treatment regimenfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination (i.e., other drugsbeing administered to the patient) and the severity of the particulardisease undergoing therapy, as well as the judgment of the prescribingmedical practitioner. In general, the use of the minimum dose sufficientto provide effective therapy is preferred. Patients may generally bemonitored for therapeutic effectiveness using medical or veterinarycriteria suitable for the condition being treated or prevented.

Combinations

A concomitant medicine comprising the compounds of the presentdisclosure and other drug may be administered as a combinationpreparation in which both components are contained in a singleformulation, or administered as separate formulations. Theadministration by separate formulations includes simultaneousadministration and administration with some time intervals. In the caseof the administration with some time intervals, the compound of thepresent disclosure can be administered first, followed by another drugor another drug can be administered first, followed by the compound ofthe present disclosure. The administration method of the respectivedrugs may be the same or different.

The dosage of the other drug can be properly selected, based on a dosagethat has been clinically used. The compounding ratio of the compound ofthe present disclosure and the other drug can be properly selectedaccording to age and weight of a subject to be administered,administration method, administration time, disorder to be treated,symptom and combination thereof. For example, the other drug may be usedin an amount of 0.01 to 100 parts by mass, based on 1 part by mass ofthe compound of the present disclosure. The other drug may be acombination of two or more kind of arbitrary drugs in a properproportion.

The compounds described herein may be used or combined with one or moretherapeutic agent such as an antimicrobial agent, an antiviral agent, acytotoxic agent, a gene expression modulatory agent, a chemotherapeuticagent, an anti-cancer agent, an anti-angiogenic agent, animmunotherapeutic agent, an anti-hormonal agent, an anti-fibrotic agent,radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent. These therapeutic agents may be in the formsof compounds, antibodies, polypeptides, or polynucleotides.

The compounds described herein may be used or combined with one or moreof a therapeutic antibody, a bispecific antibody and “antibody-like”therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®,TandAbs®, Fab derivatives), an antibody-drug conjugate (ADC), a virus,an oncolytic virus, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), aCAR (chimeric antigen receptor) T-cell immunotherapeutic agent, or anycombination thereof.

Examples of chemotherapeutics include an alkylation agent, nitrosoureaagent, antimetabolite, anticancer antibiotics, vegetable-originalkaloid, topoisomerase inhibitor, hormone drug, hormone antagonist,aromatase inhibitor, P-glycoprotein inhibitor, platinum complexderivative, other immunotherapeutic drugs and other anticancer drugs.

The compounds described herein may be used or combined with a cancertreatment adjunct, such as a leucopenia (neutropenia) treatment drug,thrombocytopenia treatment drug, antiemetic and cancer pain interventiondrug, concomitantly or in a mixture form.

The compounds described herein may be used or combined with a kinaseinhibitor.

In one embodiment, the compounds of the present disclosure can be usedwith other immunomodulators and/or a potentiating agent concomitantly orin a mixture form. Examples of the immunomodulator include variouscytokines, vaccines and adjuvants. Examples of these cytokines, vaccinesand adjuvants that stimulates immune responses include but not limitedto GM-CSF, M-CSF, G-CSF, interferon-a, beta, or gamma, IL-1, IL-2, IL-3,IL-12, Poly (I:C) and CPG. The potentiating agents includecyclophosphamide and analogs of cyclophosphamide, anti-TGF and imatinib(Gleevac), a mitosis inhibitor, such as paclitaxel, Sunitinib (Sutent)or other antiangiogenic agents, an aromatase inhibitor, such asletrozole, an A2a adenosine receptor (A2AR) antagonist, an angiogenesisinhibitor, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists,and IL-18 antagonists.

In some embodiments, the compounds described herein may be used orcombined with one or more modulator of CCR1, CCR2, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5,CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In some embodiments, themodulator is an antagonist.

In some embodiments, the compounds described herein may be used orcombined with one or more chemokine and/or chemoattractant receptorantagonists described in, for example, WO2007/002667, WO2007/002293,WO/2003/105853, WO/2007/022257, WO/2007/059108, WO/2007/044804,WO2007/115232, WO2007/115231, WO2008/147815, WO2010/030815,WO2010/075257, WO2011/163640, WO2010/054006, WO2010/051561,WO2011/035332, WO2013/082490, WO2013/082429, WO2014/085490,WO2014/100735, WO2014/089495, WO2015/084842, WO2016/187393,WO2017/127409, WO 2017/087607, WO2017/087610, WO2017/176620,WO2018/222598, WO2018/222601, WO2013/130811, WO2006/076644,WO2008/008431, WO2009/038847, WO2008/008375, WO2008/008374,WO2008/010934, WO2009/009740, WO2005/112925, WO2005/112916,WO2005/113513, WO2004/085384, WO2004/046092. Chemokine and/orchemoattractant receptor antagonists useful in the present disclosurealso include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664,CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430,CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022and/or CCX3384.

Dosage

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orpreventions of conditions involving the PD-1/PD-L1 interaction (about0.5 mg to about 7 g per human patient per day). The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Dosage unit forms will generallycontain between from about 1 mg to about 500 mg of an active ingredient.For compounds administered orally, transdermally, intravaneously, orsubcutaneously, it is preferred that sufficient amount of the compoundbe administered to achieve a serum concentration of 5 ng(nanograms)/mL-10 μg (micrograms)/mL serum, more preferably sufficientcompound to achieve a serum concentration of 20 ng-1 μg/ml serum shouldbe administered, most preferably sufficient compound to achieve a serumconcentration of 50 ng/ml-200 ng/ml serum should be administered. Fordirect injection into the synovium (for the treatment of arthritis)sufficient compounds should be administered to achieve a localconcentration of approximately 1 micromolar.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily, three times daily, or less ispreferred, with a dosage regimen of once daily or 2 times daily beingparticularly preferred. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, and rate of excretion, drugcombination (i.e., other drugs being administered to the patient), theseverity of the particular disease undergoing therapy, and otherfactors, including the judgment of the prescribing medical practitioner.

In another aspect of the disclosure, the compounds of the disclosure canbe used in a variety of non-pharmaceutical in vitro and in vivoapplication. The compounds of the disclosure may also be used aspositive controls in assays for PD-1/PD-L1 interaction activity, i.e.,as standards for determining the ability of a candidate agent to bind toPD-1 and/or PD-L1, or as radiotracers for positron emission tomography(PET) imaging or for single photon emission computerized tomography(SPECT).

Also within the scope of the present disclosure are kits comprising acompound of the present disclosure or pharmaceutically acceptable saltsthereof and instructions for use. The kit can further contain at leastone additional reagent. Kits typically include a label indicating theintended use of the contents of the kit. The term label includes anywriting, or recorded material supplied on or with the kit, or whichotherwise accompanies the kit.

EXAMPLES

The following Examples illustrate various methods of making compounds ofthis disclosure including compounds of Formulae (I), (Ia) or (Ib). Thefollowing examples are offered to illustrate, but not to limit theclaimed disclosure.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR spectra wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare provided relative to TMS and are tabulated in the order:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet) and number of protons. Mass spectrometry results are reportedas the ratio of mass over charge. In the examples, a single m/z value isreported for the M+H (or, as noted, M−H) ion containing the most commonatomic isotopes. Isotope patterns correspond to the expected formula inall cases. Electrospray ionization (ESI) mass spectrometry analysis wasconducted on a Hewlett-Packard MSD electrospray mass spectrometer usingthe HP1100 HPLC for sample delivery. Normally the analyte was dissolvedin methanol or CH₃CN at 0.1 mg/mL and 1 microliter was infused with thedelivery solvent into the mass spectrometer, which scanned from 100 to1000 Daltons. All compounds could be analyzed in the positive ornegative ESI mode, using acetonitrile/water with 1% formic acid as thedelivery solvent.

The following abbreviations are used in the Examples and throughout thedescription of the disclosure: TLC means Thin layer chromatography.

Compounds within the scope of this disclosure can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thisdisclosure, and that the approaches described within the body of thisdocument are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed unless a specific enantiomer is specified.

The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Example 1:(S)-5-((((5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)amino)methyl)pyrrolidin-2-one

Step a: A mixture of2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (10 g,39.44 mmol), 1,3-dibromo-2-chlorobenzene (32 g, 118.3 mmol), K₂CO₃(18.53 g, 134 mmol) and Pd(dppf)Cl₂ complex with DCM (3.22 g, 3.94 mmol)in dioxane (200 mL) and water (30 mL) was stirred under N₂ at 90° C. for3 h. The contents were cooled to room temperature and purified by silicagel flash chromatography to afford3′-bromo-2,2′-dichloro-[1,1′-biphenyl]-3-amine. MS: (ES) m/z calculatedfor C₁₂H₉BrCl₂N [M+H]⁺ 315.9, found 315.9.

Step b: A mixture of 5-chloropyrido[3,4-b]pyrazine (7.20 g, 22.7 mmol),3′-bromo-2,2′-dichloro-[1,1′-biphenyl]-3-amine (3.76 g, 22.7 mmol), andCs₂CO₃ (11.09 g, 34 mmol) in DMSO (80 mL) was stirred at 75° C.overnight. The contents were cooled to room temperature, diluted withEtOAc and filtered over a plug of Celite©. The filtrate was collected,washed with water and purified by silica gel flash chromatography toaffordN-(3′-bromo-2,2′-dichloro-[1,1′-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine.MS: (ES) m/z calculated for C₁₉H₁₂BrCl₂N₄ [M+H]⁺ 445.0, found 445.0.

Step c: A mixture ofN-(3′-bromo-2,2′-dichloro-[1,1′-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine(4.88 g, 10.94 mmol),4,4,4′,4,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.05 g, 12mmol), KOAc (2.68 g, 27.35 mmol), and Pd(dppf)Cl₂ complex with DCM (893mg, 1.09 mmol) in dioxane (100 mL) was stirred under N₂ at 100° C. for10 h. The contents were cooled to room temperature and purified bysilica gel flash chromatography to affordN-(2,2′-dichloro-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine.MS: (ES) m/z calculated for C₂₅H₂₄BCl₂N₄O₂ [M+H]⁺ 493.1, found 492.9.

Step d: A mixture ofN-(2,2′-dichloro-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine(340 mg, 0.69 mmol), 5-bromo-3-methoxypyrazine-2-carbaldehyde (180 mg,0.83 mmol), K₂CO₃ (238 mg, 1.73 mmol) and Pd(dppf)Cl₂ complex with DCM(81 mg, 0.10 mmol) in dioxane (5 mL) and water (0.75 mL) was stirredunder N₂ at 90° C. for 3 h. The contents were cooled to room temperatureand purified by silica gel flash chromatography to afford5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazine-2-carbaldehyde.MS: (ES) m/z calculated for C₂₅H₁₇C₂N₆O₂ [M+H]⁺ 503.1, found 503.0.

Step e: A mixture of5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazine-2-carbaldehyde(40 mg, 0.080 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride(15 mg, 0.10 mmol), Et₃N (15 mg, 0.15 mmol) and AcOH (90 mg, 1.5 mmol)in EtOH (1 mL) and DCM (1 mL) was heated at 65° C. for 0.5 h. Thecontents were cooled to room temperature and NaBH(OAc)₃ (45 mg, 0.71mmol) was added. After stirring for 30 min the reaction was quenchedwith sat. NaHCO₃ and extracted with DCM. The organic layer was collectedand concentrated in vacuo. The obtained residue was purified by silicagel flash chromatography followed by preparative HPLC to give(S)-5-((((5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 9.25 (s, 1H), 9.06 (s, 1H), 8.54 (s, 1H), 8.03(d, J=7.6 Hz, 1H), 7.93 (d, J=6.4 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.68(dd, J=7.6, 7.6 Hz, 1H), 7.61 (dd, J=7.6, 7.6 Hz, 1H), 7.53 (m, 2H),7.47 (d, J=6.8 Hz, 1H), 4.53 (s, 2H), 4.12 (s, 2H), 4.11 (s, 3H),3.41-3.21 (m, 1H), 2.50-2.32 (m, 3H), 2.04-1.92 (m, 1H). MS: (ES) m/zcalculated C₃₀H₂₇Cl₂N₈O₂ [M+H]⁺ 601.2, found 600.9.

Example 2:(R)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidin-3-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (R)-pyrrolidin-3-ol hydrochloride using a procedure similar toExample 1. The crude material was purified by silica gel columnchromatography to give(R)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidin-3-ol.¹H NMR (400 MHz, CD₃OD) δ 8.81 (dd, J=4.2, 1.5 Hz, 1H), 8.09-8.01 (m,2H), 7.84-7.74 (m, 2H), 7.61 (dd, J=7.6, 1.7 Hz, 1H), 7.47 (dd, J=7.6,7.6 Hz, 1H), 7.41-7.31 (m, 2H), 7.26 (d, J=7.5 Hz, 1H), 7.14-7.07 (m,1H), 4.38 (m, 1H), 4.00 (s, 3H), 3.89-3.75 (m, 2H), 2.94 (ddd, J=16.8,9.4, 6.7 Hz, 2H), 2.71 (ddd, J=23.4, 10.2, 4.7 Hz, 2H), 2.57 (s, 3H),2.15 (s, 4H), 1.78 (d, J=8.7 Hz, 1H). MS: (ES) m/z calculated forC₃₂H₃₂ClN₆O₂ [M+H]⁺ 567.2, found 567.5.

Example 3:(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

Step a: To a stirred solution ofN-(2′-chloro-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine(370 mg, 0.76 mmol), 6-chloro-2-methoxynicotinaldehyde (160 mg, 0.91mmol), and K₃PO₄ (570 mg, 2.7 mmol) in a 1:1 solution of 1,4-dioxane/H₂O(8 mL) under N₂ was added Pd(PPh₃)₄ (110 mg, 0.091 mmol). After stirringat 90° C. for 16 h, the mixture was diluted with H₂O and extracted withEtOAc. The combined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography to give6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde.MS: (ES) m/z calculated for C₂₈H₂₃ClN₅O₂ [M+H]⁺ 496.2, found 496.2.

Step b: To a stirred solution of6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(53 mg, 0.106 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride(64 mg, 0.42 mmol), and triethylamine (60 μL, 0.42 mmol) in a 4:1solution of DCM/MeOH (2 mL) was added NaBH(OAc)₃ (230 mg, 1.1 mmol).After stirring for 30 min, the mixture was filtered through Celite andthe volatiles were removed in vacuo. The crude residue was purified bysilica gel column chromatography to give the desired product(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.72 (dd, J=4.3, 1.5 Hz, 1H),8.58 (dd, J=8.2, 1.3 Hz, 1H), 8.09 (dd, J=8.4, 1.5 Hz, 1H), 7.67 (dd,J=8.5, 4.2 Hz, 1H), 7.63 (dd, J=7.7, 1.8 Hz, 1H), 7.58 (d, J=7.4 Hz,1H), 7.42 (d, J=7.6 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.29 (dd, J=7.5,1.8 Hz, 1H), 7.26 (d, J=1.3 Hz, 1H), 7.09-7.03 (m, 1H), 6.42 (s, 1H),4.02 (s, 3H), 3.80 (s, 2H), 3.78-3.71 (m, 1H), 2.78 (dd, J=12.0, 4.2 Hz,1H), 2.72 (s, 3H), 2.57 (dd, J=12.0, 8.5 Hz, 1H), 2.39-2.32 (m, 3H),2.26 (s, 3H), 2.25-2.16 (m, 1H), 1.83-1.67 (m, 1H). MS: (ES) m/zcalculated for C₃₃H₃₃ClN₇O₂ [M+H]⁺ 594.2, found 594.2.

Example 4:N-(3′-(5-((((1H-imidazol-2-yl)methyl)amino)methyl)-6-methoxypyridin-2-yl)-2′-chloro-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (1H-imidazol-2-yl)methanamine hydrochloride using a proceduresimilar to step e in Example 1. The product was purified by preparativeHPLC to give the desired productN-(3′-(5-((((1H-imidazol-2-yl)methyl)amino)methyl)-6-methoxypyridin-2-yl)-2′-chloro-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine.¹H NMR (400 MHz, CDCl₃) δ 9.84 (s, 1H), 8.93 (dd, J=4.3, 1.4 Hz, 1H),8.73 (dd, J=8.6, 1.4 Hz, 1H), 8.15 (d, J=8.1 Hz, 1H), 7.92 (dd, J=8.6,4.3 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.65 (dd, J=7.7, 1.7 Hz, 1H), 7.48(d, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.34 (dd, J=7.6, 1.7 Hz, 2H),7.31 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 4.06 (s, 3H), 2.89 (s, 3H),2.24 (s, 3H). MS. (ES) m/z calculated for C₃₂H₃₀ClN₈O [M+H]⁺ 577.2,found 577.2.

Example 5:N-(3′-(5-(((2-(1H-imidazol-1-yl)ethyl)amino)methyl)-6-methoxypyridin-2-yl)-2′-chloro-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 2-(1H-imidazol-1-yl)ethan-1-amine dihydrochloride using a proceduresimilar to step e in Example 1. The product was purified by preparativeHPLC to give the desired productN-(3′-(5-(((2-(1H-imidazol-1-yl)ethyl)amino)methyl)-6-methoxypyridin-2-yl)-2′-chloro-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine.¹H NMR (400 MHz, CDCl₃) δ 9.90 (s, 1H), 9.23 (s, 1H), 8.97-8.88 (m, 1H),8.70 (d, J=8.5 Hz, 1H), 8.10-8.03 (m, 1H), 7.90 (dd, J=8.6, 4.4 Hz, 1H),7.73 (d, J=7.6 Hz, 1H), 7.58 (dd, J=7.6, 1.1 Hz, 1H), 7.49-7.39 (m, 3H),7.32 (dd, J=7.6, 1.1 Hz, 1H), 7.23 (dd, J=7.5, 2.3 Hz, 2H), 7.18 (s,1H), 4.81-4.72 (m, 2H), 4.23 (s, 2H), 3.98 (s, 3H), 3.75-3.64 (m, 2H),2.86 (s, 3H), 2.19 (s, 3H). MS: (ES) m/z calculated for C₃₃H₃₂ClN₈O[M+H]⁺ 591.2, found 591.2.

Example 6:(S)-5-((((6-(2,2′-dichloro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

The compound was prepared from6-(2,2′-dichloro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a proceduresimilar to step e in Example 1. The product was purified by silica gelcolumn chromatography to give the desired product(S)-5-((((6-(2,2′-dichloro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (s, 1H), 8.92 (d, J=4.1 Hz, 1H),8.88-8.80 (m, 1H), 8.24-8.16 (m, 1H), 7.96-7.90 (m, 1H), 7.87-7.80 (m,1H), 7.69 (s, 1H), 7.60-7.53 (m, 2H), 7.45 (d, J=7.2 Hz, 1H), 7.30 (d,J=7.4 Hz, 1H), 7.23 (dd, J=7.7, 5.9 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H),3.93 (s, 3H), 3.75 (s, 2H), 3.66 (s, 1H), 2.64 (s, 3H), 2.59 (s, 1H),2.30 (s, 2H), 2.19-2.04 (m, 3H), 1.70 (dt, J=14.2, 7.7 Hz, 1H). MS: (ES)m/z calculated for C₃₂H₃₀Cl₂N₇O₂ [M+H]⁺ 614.2, found 614.2.

Example7:1-((6-(2,2′-dichloro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylicacid

The compound was prepared from6-(2,2′-dichloro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 3-methylazetidine-3-carboxylic acid using a procedure similar tostep e in Example 1. The product was purified by silica gel columnchromatography to give the desired product1-((6-(2,2′-dichloro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 9.99 (s, 1H), 9.12 (d, J=8.4 Hz, 1H),8.78 (d, J=4.2 Hz, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.87 (s, 1H), 7.68 (dd,J=17.8, 7.8 Hz, 2H), 7.50 (m, 2H), 7.37-7.28 (m, 2H), 7.08 (d, J=7.3 Hz,1H), 4.36 (s, 2H), 4.08-4.00 (m, 5H), 3.39 (d, J=12.8 Hz, 2H), 2.79 (s,3H), 1.46 (s, 3H), 1.31 (d, J=6.4 Hz, 2H). MS: (ES) m/z calculated forC₃₂H₂₉Cl₂N₆O₂ [M+H]⁺ 615.2, found 615.2.

Example 8:(1S,2S)-2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)cyclobutan-1-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (1S,2S)-2-aminocyclobutan-1-ol using a procedure similar to step ein Example 1. The product was purified by preparative HPLC to give thedesired product(1S,2S)-2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)cyclobutan-1-ol.¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (d, J=4.4 Hz, 1H), 8.89 (s, 1H), 8.22(d, J=8.5 Hz, 1H), 8.05 (dd, J=8.5, 4.4 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H),7.68-7.61 (m, 2H), 7.58 (dd, J=7.6, 7.6 Hz, 1H), 7.48-7.36 (m, 3H), 7.23(d, J=7.6 Hz, 1H). 4.50-4.40 (m, 1H), 4.17-4.03 (m, 2H), 4.01-3.92 (m,3H), 3.80-3.67 (m, 1H), 2.55 (s, 3H), 2.20-2.07 (m, 2H), 2.04 (s, 3H),1.99-1.82 (m, 2H). MS: (ES) m/z calculated for C₃₂H₃₂ClN₆O₂ [M+H]⁺567.2, found 567.5.

Example 9:(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-ethoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-ethoxynicotinaldehydeand (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a proceduresimilar to step e in Example 1. The product was purified by preparativeHPLC to give the desired product(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-ethoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CDCl₃) δ 9.86 (s, 1H), 8.96-8.89 (m, 1H), 8.68 (d,J=8.5 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 8.05 (s, 1H), 7.92 (dd, J=8.6,4.4 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.62 (dd, J=7.7, 1.7 Hz, 1H),7.50-7.40 (m, 2H), 7.35-7.29 (m, 2H), 4.51 (q, J=7.0 Hz, 2H), 4.35-4.24(m, 2H), 4.22-4.07 (m, 1H), 3.24-3.03 (m, 2H), 2.86 (s, 3H), 2.42-2.26(m, 2H), 2.22 (s, 3H), 1.41 (t, J=7.0 Hz, 3H), 1.25 (s, 2H). MS: (ES)m/z calculated for C₃₄H₃₅ClN₇O₂ [M+H]⁺ 608.3, found 608.3.

Example 10:(S)-5-((((6-(2,2′-dichloro-3′-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

Step a: To a stirred solution of 4-chloropyrido[3,2-d]pyrimidine (600mg, 3.6 mmol) and2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (920 mg,3.6 mmol) in 7 mL of MeCN was added AcOH (0.68 mL, 12 mmol). Thereaction stirred for 30 min, then the volatiles were removed in vacuo.The crude residue was purified by silica gel column chromatography togiveN-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrido[3,2-d]pyrimidin-4-amine.MS: (ES) m/z calculated for C₁₉H₂₁BClN₄O₂ [M+H]⁺ 383.1, found 383.2.

Step b: To a stirred solution ofN-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrido[3,2-d]pyrimidin-4-amine(550 mg, 1.4 mmol), 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde(470 mg, 1.4 mmol), and K₂CO₃ (710 mg, 4.9 mmol) in a 1:1 solution ofdioxane/H₂O (14 mL) under N₂ was added Pd(dppf)Cl₂ complex with DCM (140mg, 0.17 mmol). The mixture was stirred at 90° C. under N₂ for 4 h, thendiluted with H₂O. The aqueous mixture was extracted with CHCl₃ and thecombined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography to give6-(2-chloro-2′-methyl-3′-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde.MS: (ES) m/z calculated for C₂₆H₁₈Cl₂N₅O2 [M+H]⁺ 502.1, found 502.1.

Step c: To a stirred solution of6-(2,2′-dichloro-3′-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(58 mg, 0.12 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride(72 mg, 0.48 mmol), and trimethylamine (64 μL, 0.46 mmol) in a 4:1solution of DCM/MeOH (2.5 mL) was added NaBH(OAc)₃ (240 mg, 1.2 mmol).After 30 min, the mixture was filtered through Celite and the filtratewas concentrated. The product was purified by preparative HPLC to givethe desired product(S)-5-((((6-(2,2′-dichloro-3′-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CDCl₃) δ 10.01 (s, 1H), 9.07-8.98 (m, 1H), 8.86 (d,J=2.3 Hz, 2H), 8.22 (d, J=8.4 Hz, 1H), 7.81-7.71 (m, 2H), 7.68 (d, J=7.6Hz, 1H), 7.50-7.27 (m, 2H), 7.37-7.27 (m, 2H), 7.10 (d, J=7.4 Hz, 1H),7.00 (s, 1H), 4.05 (d, J=1.9 Hz, 3H), 3.98 (s, 3H), 3.02-2.65 (m, 3H),2.40-2.20 (m, 3H), 1.76 (d, J=8.6 Hz, 1H). MS: (ES) m/z calculated forC₃₁H₂₈Cl₂N₇O₂ [M+H]⁺ 600.2, found 600.2.

Example 11:(S)-5-((((6-(2-chloro-2′-methyl-3′-((7-methylpyrido[3,4-b]pyrazin-5-yl)amino)-[1,1′-biphenyl]-3-yl)-2-hydroxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

Step a: To a stirred suspension of 2,4-dichloro-6-methyl-3-nitropyridine(2.5 g, 12 mmol) in 24 mL of THE was added a solution of 7N NH₃ in MeOH(14 mL, 98 mmol). After stirring for 3 h, the volatiles were removed invacuo. The crude residue was purified by silica gel columnchromatography to give 2-chloro-6-methyl-3-nitropyridin-4-amine.C₆H₇CN₃O₂ [M+H]⁺ 188.0, found 188.0.

Step b: To a stirred mixture of 2-chloro-6-methyl-3-nitropyridin-4-amine(760 mg, 4.1 mmol) and Fe (1.1 g, 20 mmol) in a 5:1 solution of EtOH/H₂O(24 mL) was added 4.4 mL of conc. HCl. The contents were refluxed for 30min, then cooled to room temperature and quenched with 100 mL of sat.NaHCO₃ (aq). The mixture was extracted with EtOAc and the combinedorganic layers were dried over MgSO₄, filtered, and concentrated invacuo to yield 2-chloro-6-methylpyridine-3,4-diamine. MS: (ES) m/zcalculated for C₆H₉ClN₃ [M+H]⁺ 158.0, found 158.0.

Step c: To a stirred solution of 2-chloro-6-methylpyridine-3,4-diamine(0.49 g, 3.1 mmol) in 3 mL of EtOH was added a 40% w/w aqueous solutionof glyoxal (2.0 mL, 12 mmol). After refluxing for 16 h, the mixture wasdiluted with H₂O and extracted with EtOAc. The organic layers werecombined, dried over MgSO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel column chromatography to give5-chloro-7-methylpyrido[3,4-b]pyrazine. MS: (ES) m/z calculated forC₈H₇ClN₃ [M+H]⁺ 180.0, found 180.1.

Step d: To a stirred solution of 5-chloro-7-methylpyrido[3,4-b]pyrazine(200 mg, 1.0 mmol) and2′-chloro-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-amine(350 mg, 1.0 mmol) in 2 mL of MeCN was added AcOH (0.18 mL, 3.1 mmol).After 30 min, the volatiles were concentrated in vacuo. The cruderesidue was purified by silica gel column chromatography to giveN-(2′-chloro-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)-7-methylpyrido[3,4-b]pyrazin-5-amine.MS: (ES) m/z calculated for C₂₇H₂₉BClN₄O₂ [M+H]⁺ 487.2, found 487.2.

Step e: To a stirred solution ofN-(2′-chloro-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)-7-methylpyrido[3,4-b]pyrazin-5-amine(390 mg, 0.66 mmol), 6-chloro-2-methoxynicotinaldehyde (240 mg, 1.4mmol), and K₃PO₄ (490 mg, 2.3 mmol) in a 1:1 solution of 1,4-dioxane/H₂O(3.3 mL) under N₂ (g) was added Pd(PPh₃)₄ (76 mg, 0.066 mmol). Themixture was stirred under N₂ (g) at 90° C. for 3 h. The mixture wasdiluted with H₂O and then extracted with EtOAc. The combined organiclayers were dried over MgSO₄, filtered, and concentrated. The cruderesidue was purified by silica gel column chromatography to give6-(2-chloro-2′-methyl-3′-((7-methylpyrido[3,4-b]pyrazin-5-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde.MS: (ES) m/z calculated for C₂₈H₂₃ClN₅O₂ [M+H]⁺ 496.2, found 496.2.

Step f: To a stirred mixture of6-(2-chloro-2′-methyl-3′-((7-methylpyrido[3,4-b]pyrazin-5-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(120 mg, 0.25 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride(150 mg, 0.99 mmol), and trimethylamine (0.14 mL, 0.99 mmol) in a 4:1solution of DCM/MeOH (5 mL) was added NaBH(OAc)₃ (530 mg, 2.5 mmol).After stirring for 30 min, the mixture was filtered through Celite, andthe filtrate was concentrated in vacuo. The product was purified bypreparative HPLC to give the product(S)-5-((((6-(2-chloro-2′-methyl-3′-((7-methylpyrido[3,4-b]pyrazin-5-yl)amino)-[1,1′-biphenyl]-3-yl)-2-hydroxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 9.32 (s, 1H), 9.07 (d, J=2.0Hz, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.23 (d, J=8.7 Hz, 1H), 7.76 (d, J=7.0Hz, 1H), 7.62 (s, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.50-7.43 (m, 1H), 7.35(dd, J=7.9, 7.9 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J=7.5 Hz, 1H), 6.55 (s,2H), 6.43 (d, J=7.1 Hz, 1H), 4.07 (s, 3H), 3.95-3.84 (m, 1H), 2.48 (s,4H), 2.26-2.15 (m, 3H), 2.11 (s, 3H), 1.86-1.70 (m, 1H). MS: (ES) m/zcalculated for C₃₂H₃₁ClN₇O₂ [M+H]⁺ 580.2, found 580.1.

Example 12:(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

Step a: To a stirred solution of 3-aminopicolamide (5.0 g, 36 mmol) andpyridine (4.4 mL, 55 mmol) in 70 mL of DCM at −78° C. under N₂ was addeddropwise trifluoroacetic anhydride (7.7 mL, 55 mmol). The reaction wasstirred at room temperature for 18 h. The volatiles were removed toyield 3-(2,2,2-trifluoroacetamido)picolinamide. MS: (ES) m/z calculatedfor C₈H₇F₃N₃O₂ [M+H]⁺ 234.0, found 234.1.

A solution of 3-(2,2,2-trifluoroacetamido)picolinamide and pyridine (7.7mL, 55 mmol) in 35 mL of 1,2-dichloroethane was stirred at 115° C. for72 h. The mixture was cooled to room temperature and quenched with asolution of NaCl (aq). The layers were separated and the aqueous layerwas extracted with a solution of 10% MeOH in DCM. The combined organiclayers were dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude residue was purified by silica gel column chromatography to yield2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(1H)-one. MS: (ES) m/zcalculated for C₈H₅F₃N₃O [M+H]⁺ 216.0, found 216.0.

Step b: To a stirred solution of2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(1H)-one (2.5 g, 11 mmol) in50 mL of DCM under N₂ was added 0.2 mL of DMF followed by dropwiseaddition of oxalyl chloride (1.4 mL, 17 mmol). After stirring for 18 h,the volatiles were removed in vacuo. The crude residue was purified bysilica gel column chromatography to give4-chloro-2-(trifluoromethyl)pyrido[3,2-d]pyrimidine. MS: (ES) m/zcalculated for C₈H₄ClF₃N₃ [M+H]⁺ 234.0, found 234.0.

Step c: To a stirred solution of4-chloro-2-(trifluoromethyl)pyrido[3,2-d]pyrimidine (1.9 g, 8.0 mmol)and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.9mg, 8.0 mmol) in 16 mL of MeCN was added AcOH (1.4 mL, 24 mmol). After30 min, the volatiles were concentrated in vacuo. The crude residue waspurified by silica gel column chromatography to giveN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-amine.MS: (ES) m/z calculated for C₂₁H₂₃BF₃N₄O₂ [M+H]⁺ 431.2, found 431.2.

Step d: To a stirred solution ofN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-amine(730 mg, 1.7 mmol), 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde(590 mg, 1.9 mmol), and K₂CO₃ (690 mg, 5.0 mmol) in a 1:1 solution of1,4-dioxane/H₂O under N₂ was added Pd(dppf)Cl₂ complex with DCM (160 mg,0.20 mmol). The mixture was stirred at 90° C. under N₂ for 4 h, thendiluted with 100 mL of H₂O. The contents were extracted with EtOAc andthe combined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography to give6-(2-chloro-2′-methyl-3′-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde.MS: (ES) m/z calculated for C₂₈H₂₀ClF₃N₅O₂ [M+H]⁺ 550.1, found 550.1.

Step e: To a stirred solution of6-(2-chloro-2′-methyl-3′-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(200 mg, 0.36 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride(220 mg, 1.5 mmol), and trimethylamine (0.21 mL, 1.5 mmol) in a 4:1solution of DCM/MeOH (7 mL) was added NaBH(OAc)₃ (760 mg, 3.6 mmol).After stirring for 30 min, the mixture was filtered through Celite, thefiltrate concentrated in vacuo. The product was purified by preparativeHPLC to give the desired product(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CDCl₃) δ 9.50 (s, 1H), 8.91 (dd, J=4.3, 1.5 Hz, 1H),8.59-8.53 (m, 1H), 8.33 (dd, J=8.5, 1.5 Hz, 1H), 7.83 (dd, J=8.5, 4.3Hz, 1H), 7.66 (dd, J=7.7, 1.8 Hz, 1H), 7.59 (d, J=7.4 Hz, 1H), 7.44 (t,J=7.7 Hz, 2H), 7.31 (dd, J=7.5, 1.8 Hz, 1H), 7.29 (m, 1H), 7.12 (dd,J=7.6, 1.2 Hz, 1H), 5.99 (s, 1H), 4.04 (s, 3H), 3.81 (s, 2H), 3.76 (d,J=13.4 Hz, 1H), 2.81 (dd, J=12.0, 4.2 Hz, 1H), 2.57 (dd, J=12.0, 8.7 Hz,1H), 2.41-2.33 (m, 2H), 2.29 (s, 3H), 2.28-2.19 (m, 1H), 1.84-1.71 (m,1H). MS: (ES) m/z calculated for C₃₃H₃₀ClF₃N₇O₂ [M+H]⁺ 648.2, found648.2.

Example 13:1-((6-(2-chloro-2′-methyl-3′-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 3-methylazetidine-3-carboxylic acid using a procedure similar tostep e in Example 1. The product was purified by silica gel columnchromatography to give the desired product1-((6-(2-chloro-2′-methyl-3′-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 9.48 (s, 1H), 8.89 (d, J=4.4 Hz, 1H),8.55 (d, J=8.1 Hz, 1H), 8.31 (d, J=8.5 Hz, 1H), 7.89 (s, 1H), 7.81 (dd,J=8.4, 4.4 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.41 (dd, J=7.8, 7.8 Hz,2H), 7.30 (d, J=7.4 Hz, 2H), 7.09 (d, J=7.7 Hz, 1H), 4.42 (s, 1H), 4.09(s, 1H), 4.02 (s, 3H), 3.43 (s, 2H), 2.28-2.23 (m, 8H). MS: (ES) m/zcalculated for C₃₃H₂₉ClF₃N₆O₃ [M+H]⁺ 649.2, found 649.5.

Example 14:(S)-5-((((6-(2-chloro-3′-((2-isopropylpyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

Step a: To a stirred solution of 3-aminopicolamide (2.5 g, 18 mmol) andtriethylamine (5.8 mL, 42 mmol) in a 3:1 solution of DCM/THF (80 mL)under N₂ was added dropwise isobutyryl chloride (2.9 mL, 27 mmol). Thereaction mixture was stirred at room temperature for 3.5 h, thenadjusted to pH=7 with 1N HCl (aq). The contents were extracted with DCMand concentrated. The crude residue was diluted with EtOH and stirredwith NaOH (3.8 g, 54 mmol). After 6 h, the mixture was neutralized witha solution of AcOH in H₂O, then extracted with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by silica gel column chromatography toyield 2-isopropylpyrido[3,2-d]pyrimidin-4(1H)-one. MS: (ES) m/zcalculated for C₁₀H₁₂N₃O [M+H]⁺ 190.1, found 190.2.

Step b: To a solution of 2-isopropylpyrido[3,2-d]pyrimidin-4(1H)-one(2.0 g, 11 mmol) in DCM (70 mL) under N₂ was added oxalyl chloride (1.1mL, 13 mmol) followed by DMF (4 drops). After stirring at roomtemperature for 4 h, the volatiles were removed in vacuo. The residuewas purified by silica gel column chromatography to give4-chloro-2-isopropylpyrido[3,2-d]pyrimidine. MS: (ES) m/z calculated forC₁₀H₁₁ClN₃ [M+H]⁺ 208.1, found 208.1.

Step c: To a stirred mixture of4-chloro-2-isopropylpyrido[3,2-d]pyrimidine (180 mg, 0.85 mmol) and2′-chloro-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-amine(300 mg, 0.87 mmol) in 1.7 mL of MeCN was added AcOH (0.15 mL, 2.6mmol). The mixture was stirred 1.5 h, then the volatiles wereconcentrated in vacuo. The residue was purified by silica gel columnchromatography to yieldN-(2′-chloro-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)-2-isopropylpyrido[3,2-d]pyrimidin-4-amine.MS: (ES) m/z calculated for C₂₉H₃₃BClN₄O₂ [M+H]⁺ 515.2, found 515.2.

Step d: To a stirred mixture ofN-(2′-chloro-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)-2-isopropylpyrido[3,2-d]pyrimidin-4-amine(200 mg, 0.39 mmol), 6-chloro-2-methoxynicotinaldehyde (130 mg, 0.77mmol), and K₃PO₄ (280 mg, 1.3 mmol) in a 1:1 solution of dioxane/H₂O (2mL) under N₂ (g) was added Pd(PPh₃)₄ (45 mg, 0.039 mmol). The reactionwas stirred under N₂ at 90° C. for 2 h, the cooled to room temperatureand diluted with 5 mL of H₂O. The contents were extracted with EtOAc andthe organic layers were combined, dried over MgSO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography to give6-(2-chloro-3′-((2-isopropylpyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde.MS: (ES) m/z calculated for C₃₀H₂₇ClN₅O₂ [M+H]⁺ 524.2, found 524.2.

Step e: To a stirred solution of6-(2-chloro-3′-((2-isopropylpyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(100 mg, 0.19 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride(120 mg, 0.77 mmol), and trimethylamine (0.11 mL, 0.76 mmol) in a 4:1solution of DCM/MeOH (4 mL) was added NaBH(OAc)₃ (410 mg, 1.9 mmol).After stirring for 30 min, the mixture was filtered through Celite, thenconcentrated in vacuo. The product was purified by preparative HPLC togive the desired product(S)-5-((((6-(2-chloro-3′-((2-isopropylpyrido[3,2-d]pyrimidin-4-yl)amino)-2′-methyl-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, DMSO-d₆) δ 9.06-8.90 (m, 1H), 8.73 (s, 1H), 8.26 (dd,J=8.6, 1.5 Hz, 1H), 8.04 (dd, J=8.5, 4.3 Hz, 1H), 7.96 (d, J=7.6 Hz,1H), 7.68 (d, J=8.5 Hz, 1H), 7.66 (dd, J=7.7, 1.8 Hz, 1H), 7.61 (s, 1H),7.58 (t, J=7.6 Hz, 1H), 7.45-7.38 (m, 3H), 7.23-7.18 (m, 1H), 4.30-4.17(m, 2H), 3.98 (s, 3H), 3.90 (ddd, J=6.7, 6.7, 6.7 Hz, 1H), 3.23-3.12 (m,1H), 3.12-3.02 (m, 2H), 2.27-2.12 (m, 3H), 2.03 (s, 3H), 1.87-1.68 (m,1H), 1.23 (d J=6.8 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H). MS: (ES) m/zcalculated for C₃₅H₃₇ClN₇O₂ [M+H]⁺ 622.3, found 622.3.

Example 15:N-(2′-chloro-3′-(6-methoxy-5-((methylamino)methyl)pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

A mixture of6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(50 mg, 0.10 mmol), methanamine hydrogen chloride (35 mg, 0.052 mmol)and AcOH (0.10 mL, 0.71 mmol) in DCM (2 mL) was stirred for 1.5 h atroom temperature. To the mixture was added NaBH(OAc)₃ (40 mg, 0.18mmol). After stirring for an additional 1.5 h, the reaction was quenchedwith sat. NaHCO₃ and extracted with DCM. The organic layer wasseparated, dried over Na₂SO₄, concentrated in vacuo and purified bysilica gel chromatography to yieldN-(2′-chloro-3′-(6-methoxy-5-((methylamino)methyl)pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine.¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.73 (dd, J=4.0, 1.6 Hz, 1H),8.59 (d, J=7.6 Hz, 1H), 8.09 (dd, J=8.8, 1.6 Hz, 1H), 7.66-7.58 (m, 1H),7.60 (d, J=7.2 Hz, 1H), 7.40 (dd, J=7.6, 2.0 Hz, 1H), 7.44-7.37 (m, 2H),7.31-7.24 (m, 3H), 7.06 (dd, J=7.6, 1.2 Hz, 1H), 4.03 (s, 3H), 3.76 (s,2H), 2.73 (s, 3H), 2.48 (s, 3H), 2.27 (s, 3H). MS: (ES) m/z calculatedC₂₉H₂₈ClN₆O [M+H]⁺ 511.2, found 511.5.

Example16:2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)acetamide

A mixture of6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(50 mg, 0.10 mmol), 2-aminoacetamide hydrogen chloride (30 mg, 0.27mmol), Et₃N (0.070 mL, 0.50 mmol) and AcOH (0.080 mL, 1.37 mmol) in DCM(2 mL) was stirred for 1.5 h at room temperature. To the mixture wasadded NaBH(OAc)₃ (80 mg, 0.36 mmol). After stirring for an additional1.5 h, the reaction was quenched with sat. NaHCO₃ and extracted withDCM. The organic layer was separated, dried over Na₂SO₄, concentrated invacuo and purified by silica gel chromatography to afford2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)acetamide.¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.72 (dd, J=4.0, 1.2 Hz, 1H),8.58 (d, J=8.4 Hz, 1H), 8.09 (dd, J=8.4, 1.6 Hz, 1H), 7.70-7.65 (m, 1H),7.63 (dd, J=8.0, 1.6 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.44-7.37 (m, 2H),7.30 (dd, J=5.6, 2.0 Hz, 1H), 7.32-7.24 (m, 2H), 7.06 (d, J=7.2 Hz, 1H),4.03 (s, 3H), 3.79 (s, 2H), 3.31 (s, 2H), 2.36 (s, br, 2H), 2.26 (s,3H), 2.04 (s, 3H). MS: (ES) m/z calculated C₃₀H₂₉ClN₇O₂ [M+H]⁺ 554.2,found 554.1.

Example 17:N-(2′-chloro-3′-(6-methoxy-5-(morpholinomethyl)pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

A mixture of6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(50 mg, 0.10 mmol), morpholine (30 mg, 0.57 mmol) and AcOH (80 mg, 1.37mmol) in DCM (2 mL) was stirred for 1 h at room temperature. To themixture was added NaBH(OAc)₃ (75 mg, 0.35 mmol). After stirring for anadditional 40 minutes, the reaction was quenched with sat. NaHCO₃ andextracted with DCM. The organic layer was separated, dried over Na₂SO₄,concentrated in vacuo and purified by silica gel chromatography toaffordN-(2′-chloro-3′-(6-methoxy-5-(morpholinomethyl)pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine.H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.73 (dd, J=4.4, 1.6 Hz, 1H),8.59 (d, J=8.0 Hz, 1H), 8.09 (dd, J=8.8, 1.6 Hz, 1H), 7.73 (d, J=7.2 Hz,1H), 7.70-7.63 (m, 2H), 7.44-7.37 (m, 2H), 7.31-7.25 (m, 2H), 7.06 (d,J=6.8 Hz, 1H), 4.01 (s, 3H), 3.75 (dd, J=4.8, 4.8 Hz, 4H), 3.56 (s, 2H),2.73 (s, 3H), 2.55 (dd, J=4.4, 4.4 Hz, 4H), 2.27 (s, 3H). MS. (ES) m/zcalculated C₃₂H₃₂ClN₆O₂ [M+H]⁺ 567.2, found 567.5.

Example 18:N-(2′-chloro-3′-(6-methoxy-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

A mixture of6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(60 mg, 0.12 mmol), tetrahydro-2H-pyran-4-amine (25 mg, 0.24 mmol) andAcOH (28 mg, 0.48 mmol) in DCM (1.5 mL) was stirred for 1 h at roomtemperature. To the mixture was added NaBH(OAc)₃ (88 mg, 0.41 mmol).After stirring for an additional 40 minutes, the reaction was quenchedwith sat. NaHCO₃ and extracted with DCM. The organic layer wasseparated, dried over Na₂SO₄, concentrated in vacuo and purified bysilica gel chromatography to affordN-(2′-chloro-3′-(6-methoxy-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine.¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.73 (dd, J=4.0, 1.2 Hz, 1H),8.58 (d, J=7.6 Hz, 1H), 8.09 (dd, J=8.8, 1.6 Hz, 1H), 7.70-7.61 (m, 3H),7.44-7.37 (m, 2H), 7.31-7.25 (m, 2H), 7.06 (d, J=7.2 Hz, 1H), 4.03 (s,3H), 4.04-3.96 (m, 2H), 3.84 (s, 2H), 3.41 (ddd, J=11.6, 11.6, 2.0 Hz,2H), 2.73 (s, 3H), 2.80-2.70 (m, 1H), 2.27 (s, 3H), 1.80-1.94 (m, 4H).MS: (ES) m/z calculated C₃₃H₃₄ClN₆O₂ [M+H]⁺ 581.2, found 581.5.

Example 19:(S)-5-((((5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-ethylpyrazin-2-yl)methyl)amino)methyl)pyrrolidin-2-one

Step a: A mixture of2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (15 g,59.2 mmol), 1,3-dibromo-2-chlorobenzene (48 g, 177.5 mmol), K₂CO₃ (27.8g, 201 mmol) and Pd(dppf)Cl₂ complex with DCM (4.83 g, 5.9 mmol) indioxane (300 mL) and water (45 mL) was stirred under N₂ at 90° C. for 3h. The contents were cooled to room temperature, filtered over a pad ofCelite/Na₂SO₄, concentrated in vacuo and purified by silica gelchromatography to afford 3′-bromo-2,2′-dichloro-[1,1′-biphenyl]-3-amine.

Step b: A mixture of 3′-bromo-2,2′-dichloro-[1,1′-biphenyl]-3-amine (6.0g, 14.6 mmol), 5-chloropyrido[3,4-b]pyrazine (2.42 g, 14.6 mmol) andCs₂CO₃ (7.14 g, 21.9 mmol) in DMSO (100 mL) was stirred at 75° C.overnight. The contents were cooled to room temperature, diluted withwater and EtOAC, then filtered over Celite. The organic layer of thefiltrate was separated, dried over Na₂SO₄, concentrated in vacuo andpurified by silica gel chromatography to affordN-(3′-bromo-2,2′-dichloro-[1,1′-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine.MS: (ES) m/z calculated for C₁₉H₁₂BrCl₂N₄ [M+H]⁺ 445.0, found 444.7.

Step c: A mixture ofN-(3′-bromo-2,2′-dichloro-[1,1′-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine(2.80 g, 6.3 mmol),4,4,4′,4,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.76 g, 6.94mmol), KOAc (1.55 g, 15.75 mmol), and Pd(dppf)Cl₂ complex with DCM (1.30g, 1.6 mmol) in dioxane (100 mL) was stirred under N₂ at 98° C.overnight. The contents were cooled to room temperature and filtratedover celite. The filtrate was collected, concentrated in vacuo andpurified by silica gel flash chromatography to affordN-(2,2′-dichloro-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine.MS: (ES) m/z calculated for C₂₅H₂₄BCl₂N₄O₂ [M+H]⁺ 493.1, found 493.1.

Step d: A mixture ofN-(2,2′-dichloro-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine(125 mg, 0.25 mmol), 5-bromo-3-ethylpyrazine-2-carbaldehyde (54 mg, 0.25mmol), K₃PO₄ (161 mg, 0.76 mmol) and X-PhosPdGen2 (40 mg, 0.050 mmol) inTHE (2.5 mL) and water (2.5 mL) was stirred at room temperature for 3 h.The contents were filtered over a pad of Celite and Na₂SO₄. The filtratewas collected, concentrated in vacuo and purified by silica gel flashchromatography to afford5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-ethylpyrazine-2-carbaldehyde.MS: (ES) m/z calculated for C₂₆H₁₉Cl₂N₆O [M+H]⁺ 501.1, found 501.1.

Step e: A mixture of5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-ethylpyrazine-2-carbaldehyde(40 mg, 0.080 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrogenchloride (15 mg, 0.10 mmol), Et₃N (60 mg, 0.60 mmol) and AcOH (90 mg,1.5 mmol) in EtOH (1 mL) and DCM (1 mL) was heated at 65° C. for 20 min.The contents were cooled to room temperature and NaBH(OAc)₃ (40 mg, 0.19mmol) was added then stirred for and additional 15 min. The volatileswere removed in vacuo and the obtained residue was purified by HPLC toyield(S)-5-((((5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-ethylpyrazin-2-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.97 (s, 1H), 8.83 (s, 1H), 8.57(d, J=8.4 Hz, 1H), 8.16 (d, J=6.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H),7.64-7.50 (m, 3H), 7.40 (d, J=6.8 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H),4.72-4.60 (m, 2H), 4.20-4.10 (m, 1H), 3.41-3.40 (m, 2H), 2.94 (q, J=7.6Hz, 2H), 2.50-2.32 (m, 3H), 2.04-1.90 (m, 1H), 1.40 (t, J=7.4 Hz, 3H).MS: (ES) m/z calculated C₃₁H₂₉Cl₂N₈O [M+H]⁺ 599.2, found 599.5.

Example20:1-((6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylicacid

Step a: A mixture ofN-(2,2′-dichloro-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine(250 mg, 0.50 mmol), 6-chloro-2-methoxynicotinaldehyde (94 mg, 0.55mmol), K₃PO₄ (265 mg, 2.5 mmol) and X-PhosPdGen2 (70 mg, 0.090 mmol) inTHE (4 mL) and water (4 mL) was stirred at room temperature for 5 h. Thecontents were filtered over a pad of Celite and Na₂SO₄. The filtrate wascollected, concentrated in vacuo and purified by silica gel flashchromatography to afford6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde.MS: (ES) m/z calculated for C₂₆H₁₈Cl₂N₅O₂ [M+H]⁺ 502.1, found 502.1.

Step b: A mixture of6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(40 mg, 0.080 mmol), 3-methylazetidine-3-carboxylic acid (30 mg, 0.26mmol) and AcOH (75 mg, 1.25 mmol) in DMF (1 mL) was stirred at roomtemperature. After 1 h, NaBH(OAc)₃ (70 mg, 0.33 mmol) was added and thecontents were stirred for an additional hour. The volatiles were removedin vacuo and the obtained residue was purified by HPLC to give1-((6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 9.15 (d, J=1.6 Hz, 1H), 8.97 (s, 1H),8.48 (d, J=7.6 Hz, 1H), 8.12 (d, J=6.4 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H),7.67 (d, J=8.0 Hz, 1H), 7.60-7.51 (m, 2H), 7.46-7.35 (m, 3H), 7.30 (d,J=6.8 Hz, 1H), 4.53 (d, J=14.4 Hz, 1H), 4.51 (s, 3H), 4.14 (d, J=10.8Hz, 2H), 4.08 (s, 3H), 1.61 (s, 3H). MS: (ES) m/z calculatedC₃₁H₂₇Cl₂N₆O₃ [M+H]⁺ 601.1, found 600.9.

Example 21:(S)-5-((((6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

A mixture of6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehyde(30 mg, 0.060 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrogenchloride (15 mg, 0.10 mmol), Et₃N (60 mg, 0.60 mmol) and AcOH (90 mg,1.5 mmol) in EtOH (1 mL) and DCM (1 mL) was heated at 65° C. for 30 min.The contents were cooled to room temperature and NaBH(OAc)₃ (40 mg, 0.19mmol) was added. After stirred for an additional 30 min the volatileswere removed in vacuo. The obtained residue was purified by HPLC to give(S)-5-((((6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 9.11 (s, 1H), 8.93 (s, 1H), 8.80 (d, J=7.6 Hz,1H), 8.27 (d, J=6.0 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.67 (d, J=7.6 Hz,1H), 7.56-7.49 (m, 2H), 7.46-7.37 (m, 3H), 7.17 (d, J=6.8 Hz, 1H), 4.34(s, 2H), 4.11 (s, 3H), 4.10-4.02 (m, 1H), 3.30-3.20 (m, 2H), 2.48-2.30(m, 3H), 1.96-1.84 (m, 1H). MS: (ES) m/z calculated C₃₁H₂₈Cl₂N₇O₂ [M+H]⁺600.2, found 599.8.

Example 22:(3R,4R)-4-(((5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

A mixture of5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazine-2-carbaldehyde(50 mg, 0.10 mmol), (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrogenchloride (20 mg, 0.13 mmol), Et₃N (75 mg, 0.75 mmol) and AcOH (120 mg,2.0 mmol) in EtOH (2 mL) and DCM (2 mL) was heated at 65° C. for 40 min.The contents were cooled to room temperature and NaBH(OAc)₃ (65 mg, 0.30mmol) was added. After stirred for an additional 10 min the volatileswere removed in vacuo. The obtained residue was purified by HPLC to give(3R,4R)-4-(((5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)amino)tetrahydro-2H-pyran-3-ol.¹H NMR (400 MHz, CD₃OD) δ 9.14 (d, J=1.2 Hz, 1H), 8.96 (d, J=1.6 Hz,1H), 8.58-8.56 (m, 1H), 8.54 (s, 1H), 8.15 (d, J=6.4 Hz, 1H), 7.73 (d,J=7.2 Hz, 1H), 7.62-7.54 (m, 2H), 7.51 (d, J=6.8 Hz, 1H), 7.40 (d, J=6.8Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 4.84 (s, 2H), 4.12 (s, 3H), 4.08-3.94(m, 3H), 3.64-3.53 (m, 2H), 3.46 (dd, J=11.2, 11.2 Hz, 1H), 2.24-2.10(m, 1H), 1.93 (dd, J=12.0, 3.6 Hz, 1H). MS: (ES) m/z calculatedC₃₀H₂₈Cl₂N₇O₃ [M+H]⁺ 604.2, found 603.9.

Example 23:1-((5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)azetidine-3-carboxylicacid

A mixture of5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazine-2-carbaldehyde(35 mg, 0.10 mmol), azetidine-3-carboxylic acid (25 mg, 0.25 mmol) andAcOH (60 mg, 1.0 mmol) in DMF (0.5 mL) was stirred at room temperature.After 40 min NaBH(OAc)₃ (65 mg, 0.30 mmol) was added and the contentswere stirred for an additional hour. The volatiles were removed in vacuoand the obtained residue was purified by HPLC to give1-((5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)azetidine-3-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 9.15 (d, J=1.6 Hz, 1H), 8.97 (s, 1H),8.48 (s, 1H), 8.46 (d, J=8.4 Hz, 1H), 8.11 (d, J=6.8 Hz, 1H), 7.71 (d,J=7.2 Hz, 1H), 7.60-7.55 (m, 2H), 7.50 (d, J=7.2 Hz, 1H), 7.40 (d, J=6.4Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 4.74 (s, 2H), 4.74-4.30 (m, 4H), 4.11(s, 3H), 3.84-3.72 (m, 1H). MS: (ES) m/z calculated C₂₉H₂₄Cl₂N₇O₃ [M+H]⁺588.1, found 588.0.

Example24:1-((5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)-3-methylazetidine-3-carboxylicacid

A mixture of5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazine-2-carbaldehyde(37 mg, 0.10 mmol), 3-methylazetidine-3-carboxylic acid (25 mg, 0.25mmol) and AcOH (60 mg, 1.0 mmol) in DMF (1 mL) was stirred at roomtemperature. After 1 h, NaBH(OAc)₃ (50 mg, 0.23 mmol) was added and thecontents were stirred for an additional 15 min. The volatiles wereremoved in vacuo and the obtained residue was purified by HPLC to give1-((5-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)-3-methylazetidine-3-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 9.14 (d, J=1.6 Hz, 1H), 8.96 (d, J=1.6Hz, 1H), 8.54 (d, J=8.0 Hz, 1H), 8.49 (s, 1H), 8.15 (d, J=6.0 Hz, 1H),7.71 (d, J=6.8 Hz, 1H), 7.61-7.54 (m, 2H), 7.50 (d, J=7.6 Hz, 1H), 7.40(d, J=6.4 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 4.75 (s, 2H), 4.70-4.10 (m,4H), 4.11 (s, 3H), 1.65 (s, 3H). MS: (ES) m/z calculated C₃₀H₂₆Cl₂N₇O₃[M+H]⁺ 602.1, found 602.0.

Example 25:1-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)cyclopropan-1-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 1-(aminomethyl)-cyclopropan-1-ol using a procedure similar to step ein Example 1. The crude material was purified by preparative HPLC togive the desired product1-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)cyclopropan-1-ol.¹H NMR (400 MHz, CD₃OD) S 9.03 (d, J=3.9 Hz, 1H), 8.17-8.13 (m, 1H),8.06-8.01 (m, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.66-7.62 (m, 2H), 7.53 (dd,J=8.0, 8.0 Hz, 1H) 7.46-7.38 (m, 2H), 7.36 (d, J=7.6 Hz, 1H), 7.27 (d,J=7.6 Hz, 1H), 4.37 (s, 2H), 4.09 (s, 3H), 3.20 (s, 2H), 2.65 (s, 3H),2.12 (s, 3H), 0.94-0.90 (m, 2H), 0.76-0.72 (m, 2H). MS: (ES) m/zcalculated for C₃₂H₃₂ClN₆O₂ [M+H]⁺ 567.2, found 567.5.

Example 26:3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propan-1-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 3-aminopropan-1-ol using a procedure similar to step e in Example 1.The crude material was purified by preparative HPLC to give the desiredproduct3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propan-1-ol.¹H NMR (400 MHz, CD₃OD) δ 9.05 (dd, J=4.3, 1.4 Hz, 1H), 8.17 (dd, J=8.6,1.4 Hz, 1H), 8.05 (dd, J=8.6, 4.3 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H),7.68-7.48 (m, 3H), 7.48-7.24 (m, 4H), 4.28 (s, 2H), 4.08 (s, 3H), 3.75(t, J=5.7 Hz, 2H), 3.25 (t, J=6.9 Hz, 2H), 2.65 (s, 3H), 2.12 (s, 3H),2.00-1.89 (m, 2H). MS: (ES) m/z calculated for C₃₁H₃₂ClN₆O₂ [M+H]⁺555.2, found 555.5.

Example27:1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidin-3-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 3-methylazetidin-3-ol hydrochloride using a procedure similar tostep e in Example 1. The crude material was purified by preparative HPLCto give the desired product1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidin-3-ol.¹H NMR (400 MHz, CD₃OD) δ 9.05 (dd, J=4.3, 1.4 Hz, 1H), 8.17 (dd, J=8.6,1.4 Hz, 1H), 8.05 (dd, J=8.6, 4.3 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H),7.68-7.48 (m, 3H), 7.40 (ddd, J=18.2, 16.1, 7.6 Hz, 3H), 7.28 (dd,J=7.7, 1.3 Hz, 1H), 4.52 (s, 1H), 4.46 (s, 1H), 4.22 (d, J=10.9 Hz, 2H),4.07 (s, 5H), 2.66 (s, 3H), 2.11 (s, 3H), 1.53 (s, 3H). MS: (ES) m/zcalculated for C₃₂H₃₂ClN₆O₂ [M+H]⁺ 567.2, found 567.6.

Example 28:(3R,4R)-4-(((6-(2′-chloro-2-fluoro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

The compound was prepared from6-(2′-chloro-2-fluoro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride using aprocedure similar to step e in Example 1. The crude material waspurified by preparative HPLC to give the desired product(3R,4R)-4-(((6-(2′-chloro-2-fluoro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol.¹H NMR (400 MHz, CD₃OD) δ 9.03 (dd, J=4.4, 1.4 Hz, 1H), 8.33 (dd, J=8.3,1.5 Hz, 1H), 8.24-8.15 (m, 2H), 8.04 (dd, J=8.6, 4.4 Hz, 1H), 7.87 (d,J=7.7 Hz, 1H), 7.64-7.52 (m, 2H), 7.50-7.39 (m, 3H), 4.34 (d, J=13.2 Hz,1H), 4.24 (d, J=13.3 Hz, 1H), 4.15 (s, 3H), 4.06-3.93 (m, 3H), 3.61-3.40(m, 3H), 2.75 (s, 3H), 2.16-2.03 (m, 1H), 1.86 (d, J=12.8 Hz, 1H). MS:(ES) m/z calculated for C₃₂H₃₁ClFN₆O₃ [M+H]⁺ 601.2, found 601.5.

Example 29:(S)-5-((((6-(2′-chloro-2-fluoro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

The compound was prepared from6-(2′-chloro-2-fluoro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-5-aminomethylpyrrolidin-2-one hydrochloride using a proceduresimilar to step e in Example 1. The crude material was purified bypreparative HPLC to give the desired product(S)-5-((((6-(2′-chloro-2-fluoro-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 9.04 (dd, J=4.3, 1.4 Hz, 1H), 8.32 (d, J=8.2Hz, 1H), 8.24-8.15 (m, 2H), 8.05 (dd, J=8.6, 4.3 Hz, 1H), 7.88 (d, J=7.7Hz, 1H), 7.64-7.54 (m, 2H), 7.51-7.40 (m, 3H), 4.34 (d, J=2.9 Hz, 2H),4.16 (s, 3H), 4.09-4.01 (m, 1H), 3.30-3.21 (m, 2H), 2.75 (s, 3H),2.46-2.32 (m, 3H), 1.91 (d, J=6.4 Hz, 1H). MS: (ES) m/z calculated forC₃₂H₃₀ClFN₇O₂ [M+H]⁺ 598.2, found 598.5.

Example 30:(3R,4R)-4-(((6-(2-fluoro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

The compound was prepared from6-(2-fluoro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride using aprocedure similar to step e in Example 1. The crude material waspurified by preparative HPLC to give the desired product(3R,4R)-4-(((6-(2-fluoro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol.¹H NMR (400 MHz, CD₃OD) δ 9.08-9.02 (m, 1H), 8.21-8.11 (m, 2H), 8.05(dd, J=8.6, 4.4 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.65-7.51 (m, 2H),7.50-7.34 (m, 4H), 4.34 (d, J=13.3 Hz, 1H), 4.24 (d, J=13.3 Hz, 1H),4.14 (s, 3H), 4.06-3.93 (m, 3H), 3.61-3.40 (m, 3H), 2.67 (s, 3H), 2.19(s, 3H), 2.18-2.05 (m, 1H), 1.91-1.82 (m, 1H). MS: (ES) m/z calculatedfor C₃₃H₃₄FN₆O₃ [M+H]⁺ 581.3, found 581.5.

Example 31:(S)-5-((((6-(2-fluoro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

The compound was prepared from6-(2-fluoro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a proceduresimilar to step e in Example 1. The crude product was purified bypreparative HPLC to give the desired product(S)-5-((((6-(2-fluoro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 8.83 (d, J=4.3 Hz, 1H), 8.15-7.99 (m, 3H),7.82 (dd, J=8.6, 4.3 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.48-7.33 (m, 4H),7.21 (d, J=7.5 Hz, 1H), 4.07 (s, 3H), 3.88-3.79 (m, 3H), 2.73-2.63 (m,2H), 2.59 (s, 3H), 2.38-2.23 (m, 3H), 2.23 (s, 3H), 1.81 (s, 1H). MS:(ES) m/z calculated for C₃₃H₃₃FN₇O₂ [M+H]⁺ 578.3, found 578.5.

Example 32:N-(3′-(5-((azetidin-3-ylamino)methyl)-6-methoxypyridin-2-yl)-2′-chloro-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand tert-butyl 3-aminoazetidine-1-carboxylate using a procedure similarto step e in Example 1. The crude material was purified by silica gelchromatography to give tert-butyl3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)azetidine-1-carboxylate.To the Boc-protected intermediate was added 10% TFA in DCM. The contentswere lyophilized to give the productN-(3′-(5-((azetidin-3-ylamino)methyl)-6-methoxypyridin-2-yl)-2′-chloro-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine.¹H NMR (400 MHz, CD₃OD) δ 9.05 (dd, J=4.3, 1.4 Hz, 1H), 8.21-8.09 (m,1H), 8.05 (dd, J=8.6, 4.3 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.69-7.48 (m,3H), 7.48-7.25 (m, 4H), 4.45-4.34 (m, 5H), 4.24 (s, 2H), 4.08 (s, 3H),2.66 (s, 3H), 2.12 (s, 3H). MS: (ES) m/z calculated for C₃₁H₃₁ClN₇O[M+H]⁺ 552.2, found 552.5.

Example 33:N-(2′-chloro-3′-(6-methoxy-5-((piperidin-4-ylamino)methyl)pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand tert-butyl 4-aminopiperidine-1-carboxylate using a procedure similarto step e in Example 1. The crude material was purified by silica gelchromatography to give tert-butyl4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)piperidine-1-carboxylate.The Boc-protected intermediate was treated with 10% TFA in DCM and thesolution was then lyophilized to give the pure productN-(2′-chloro-3′-(6-methoxy-5-((piperidin-4-ylamino)methyl)pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine.¹H NMR (400 MHz, CD₃OD) 9.05 (dd, J=4.4, 1.4 Hz, 1H), 8.16 (dd, J=8.6,1.4 Hz, 1H), 8.06 (dd, J=8.6, 4.3 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H),7.67-7.48 (m, 3H), 7.48-7.32 (m, 3H), 7.28 (dd, J=7.6, 1.3 Hz, 1H), 4.35(s, 2H), 4.09 (s, 3H), 3.59 (dd, J=9.9, 6.4 Hz, 3H), 3.19-3.08 (m, 2H),2.66 (s, 3H), 2.47 (d, J=13.6 Hz, 2H), 2.12 (s, 3H), 1.97 (q, J=14.2,12.4 Hz, 2H). MS: (ES) m/z calculated for C₃₃H₃₅ClN₇O [M+H]⁺ 580.3,found 580.5.

Example34:2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)ethan-1-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 2-(methylamino)ethan-1-ol using a procedure similar to step e inExample 1. The crude material was purified by silica gel chromatographyto give the product2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)ethan-1-ol.¹H NMR (400 MHz, CD₃OD) δ 8.83 (dd, J=4.3, 1.5 Hz, 1H), 8.05 (ddd,J=10.4, 8.5, 1.4 Hz, 2H), 7.86-7.75 (m, 2H), 7.62 (dd, J=7.7, 1.8 Hz,1H), 7.48 (dd, J=7.6, 7.6 Hz, 1H), 7.42-7.32 (m, 2H), 7.25 (d, J=7.5 Hz,1H), 7.16-7.09 (m, 1H), 3.99 (s, 3H), 3.72 (t, J=6.0 Hz, 2H), 3.66 (s,2H), 2.65 (t, J=6.1 Hz, 2H), 2.58 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H).MS: (ES) m/z calculated for C₃₁H₃₂ClN₆O₂ [M+H]⁺ 555.2, found 555.5.

Example 35:(S)-3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,2-diol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-3-aminopropane-1,2-diol using a procedure similar to step e inExample 1. The crude material was purified by silica gel chromatographyto give the product(S)-3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,2-diol.¹H NMR (400 MHz, CD₃OD) δ 8.83 (dd, J=4.2, 1.5 Hz, 1H), 8.10-8.00 (m,2H), 7.82 (dd, J=8.5, 4.2 Hz, 1H), 7.71 (d, J=7.4 Hz, 1H), 7.61 (dd,J=7.7, 1.7 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.42-7.32 (m, 2H), 7.24 (d,J=7.4 Hz, 1H), 7.12 (dd, J=7.6, 1.2 Hz, 1H), 4.02 (s, 3H), 3.92-3.75 (m,3H), 3.56-3.46 (m, 2H), 2.77 (dd, J=12.1, 3.8 Hz, 1H), 2.63 (dd, J=12.1,8.3 Hz, 1H), 2.58 (s, 3H), 2.16 (s, 3H). MS: (ES) m/z calculated forC₃₁H₃₂ClN₆O₃ [M+H]⁺ 571.2, found 571.5.

Example 36:(R)-3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,2-diol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (R)-3-aminopropane-1,2-diol using a procedure similar to step e inExample 1. The crude material was purified by silica gel chromatographyto give the product(R)-3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,2-diol.H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.2, 1.5 Hz, 1H), 8.05 (ddd, J=8.5,7.4, 1.4 Hz, 2H), 7.81 (dd, J=8.5, 4.2 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H),7.60 (dd, J=7.6, 1.7 Hz, 1H), 7.47 (dd, J=7.6, 7.6 Hz, 1H), 7.41-7.32(m, 2H), 7.24 (d, J=7.4 Hz, 1H), 7.15-7.08 (m, 1H), 4.02 (s, 3H),3.93-3.74 (m, 3H), 3.58-3.46 (m, 2H), 2.79 (dd, J=12.1, 3.7 Hz, 1H),2.69-2.55 (m, 1H), 2.58 (s, 3H), 2.15 (s, 3H). MS: (ES) m/z calculatedfor C₃₁H₃₂ClN₆O₃ [M+H]⁺ 571.2, found 571.5.

Example 37:(R)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (R)-3-methylpyrrolidine-3-carboxylic acid using a procedure similarto step e in Example 1. The crude material was purified by silica gelchromatography to give the product(R)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.3, 1.5 Hz, 1H), 8.05 (ddd,J=9.7, 8.3, 1.4 Hz, 2H), 7.92-7.78 (m, 2H), 7.63 (dd, J=7.7, 1.7 Hz,1H), 7.50 (dd, J=7.6, 7.6 Hz, 1H), 7.43-7.32 (m, 3H), 7.16-7.08 (m, 1H),4.49-4.36 (m, 2H), 4.10 (s, 3H), 3.71 (s, 1H), 3.50 (s, 1H), 3.38 (s,1H), 2.98 (d, J=10.7 Hz, 1H), 2.58 (s, 3H), 2.39 (s, 1H), 2.15 (s, 3H),1.96 (s, 1H), 1.34 (s, 3H). MS: (ES) m/z calculated for C₃₄H₃₄ClN₆O₃[M+H]⁺ 609.2, found 609.5.

Example 38:(R)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylpyrrolidin-3-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (R)-3-methylpyrrolidin-3-ol hydrochloride using a procedure similarto step e in Example 1. The crude material was purified by silica gelchromatography to give the product(R)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylpyrrolidin-3-ol.¹H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.3, 1.5 Hz, 1H), 8.05 (ddd,J=9.4, 8.4, 1.4 Hz, 2H), 7.86-7.75 (m, 2H), 7.61 (dd, J=7.7, 1.8 Hz,1H), 7.48 (t, J=7.6 Hz, 1H), 7.42-7.32 (m, 2H), 7.25 (d, J=7.5 Hz, 1H),7.15-7.08 (m, 1H), 4.00 (s, 3H), 3.83-3.70 (m, 2H), 2.96 (q, J=7.9 Hz,1H), 2.79-2.61 (m, 3H), 2.58 (s, 3H), 2.16 (s, 3H), 1.90 (t, J=7.0 Hz,2H), 1.36 (s, 3H). MS: (ES) m/z calculated for C₃₃H₃₄ClN₆O₂ [M+H]⁺581.2, found 581.5.

Example 39:(3R,4R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)tetrahydro-2H-pyran-3-ol

A solution of(3R,4R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol(43 mg, 0.072 mmol) and formalin (37% in water, 0.15 mL, 2.0 mmol) inMeOH (1 mL) and DCE (1 mL) was stirred at room temperature for 30 min.To the reaction was added NaBH(OAc)₃ (80 mg, 0.38 mmol). After another30 min, the mixture was quenched with water and extracted with 2:1 v/vCHCl₃:IPA. The organic phase was separated and purified by silica gelchromatography to give the product(3R,4R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)tetrahydro-2H-pyran-3-ol.¹H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.2, 1.5 Hz, 1H), 8.05 (ddd,J=8.1, 6.0, 1.4 Hz, 2H), 7.85-7.73 (m, 2H), 7.62 (dd, J=7.7, 1.8 Hz,1H), 7.48 (dd, J=7.6, 7.6 Hz, 1H), 7.42-7.32 (m, 2H), 7.25 (d, J=7.4 Hz,1H), 7.15-7.08 (m, 1H), 4.06-3.87 (m, 4H), 3.99 (s, 3H), 3.62 (d, J=13.9Hz, 1H), 3.54-3.37 (m, 2H), 2.66-2.56 (m, 1H), 2.58 (s, 3H), 2.32 (s,3H), 2.16 (s, 3H), 2.08-1.95 (m, 1H), 1.79-1.70 (m, 1H). MS: (ES) m/zcalculated for C₃₄H₃₆ClN₆O₃ [M+H]⁺ 611.3, found 611.5.

Example 40:(R)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (R)-pyrrolidine-3-carboxylic acid using a procedure similar to stepe in Example 1. The crude material was purified by silica gelchromatography to give the product(R)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidine-3-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.3, 1.5 Hz, 1H), 8.05 (ddd,J=8.2, 5.4, 1.4 Hz, 2H), 7.90 (d, J=7.6 Hz, 1H), 7.81 (dd, J=8.5, 4.2Hz, 1H), 7.63 (dd, J=7.7, 1.7 Hz, 1H), 7.50 (dd, J=7.6, 7.6 Hz, 1H),7.42-7.32 (m, 3H), 7.15-7.07 (m, 1H), 4.40 (s, 2H), 4.08 (s, 3H), 3.57(dd, J=11.3, 5.6 Hz, 1H), 3.40 (m, 3H), 3.16-3.04 (m, 1H), 2.57 (s, 3H),2.31 (m, 2H), 2.15 (s, 3H). MS: (ES) m/z calculated for C₃₃H₃₂ClN₆O₃[M+H]⁺ 595.2, found 595.5.

Example 41:2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,3-diol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 2-aminopropane-1,3-diol using a procedure similar to step e inExample 1. The crude material was purified by silica gel chromatographyto give the product2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,3-diol.¹H NMR (400 MHz, CD₃OD) δ 9.07-9.01 (m, 1H), 8.16 (dd, J=8.6, 1.4 Hz,1H), 8.05 (dd, J=8.6, 4.3 Hz, 1H), 7.94-7.87 (m, 1H), 7.68-7.58 (m, 2H),7.53 (dd, J=7.6, 7.6 Hz, 1H), 7.48-7.32 (m, 3H), 7.28 (d, J=7.6 Hz, 1H),4.41 (s, 2H), 4.09 (s, 3H), 3.90 (dd, J=12.0, 4.4 Hz, 2H), 3.80 (dd,J=11.9, 6.3 Hz, 2H), 3.38-3.32 (m, 1H), 2.65 (s, 3H), 2.12 (s, 3H). MS:(ES) m/z calculated for C₃₁H₃₂ClN₆O₃ [M+H]⁺ 571.2, found 571.5.

Example 42:2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 2-aminoethan-1-ol using a procedure similar to step e in Example 1.The crude material was purified by flash chromatography to give theproduct2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol.¹H NMR (400 MHz, CD₃OD) δ 9.06 (dd, J=4.3, 1.4 Hz, 1H), 8.16 (dd, J=8.6,1.5 Hz, 1H), 8.06 (dd, J=8.6, 4.4 Hz, 1H), 7.93-7.85 (m, 1H), 7.68-7.49(m, 3H), 7.48-7.25 (m, 4H), 4.32 (s, 2H), 4.09 (s, 3H), 3.89-3.81 (m,2H), 3.24-3.16 (m, 2H), 2.66 (s, 3H), 2.12 (s, 3H). MS: (ES) m/zcalculated for C₃₀H₃₀ClN₆O₂ [M+H]⁺ 541.2, found 541.5.

Example43:2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 2-amino-2-(hydroxymethyl)propane-1,3-diol using a procedure similarto step e in Example 1. The crude material was purified by silica gelchromatography to give the product2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol.¹H NMR (400 MHz, CD₃OD) δ 9.06 (dd, J=4.4, 1.4 Hz, 1H), 8.17 (dd, J=8.6,1.4 Hz, 1H), 8.06 (dd, J=8.6, 4.4 Hz, 1H), 7.93-7.86 (m, 1H), 7.67-7.48(m, 3H), 7.48-7.25 (m, 4H), 4.43 (s, 2H), 4.08 (s, 3H), 3.83 (s, 6H),2.66 (s, 3H), 2.12 (s, 3H). MS: (ES) m/z calculated for C₃₂H₃₄ClN₆O₄[M+H]⁺ 601.2, found 601.5.

Example 44:1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-4-methylpiperidin-4-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 4-methylpiperidin-4-ol using a procedure similar to step e inExample 1. The crude material was purified by silica gel chromatographyto give the product1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-4-methylpiperidin-4-ol.¹H NMR (400 MHz, CD₃OD) δ 9.06 (dd, J=4.3, 1.5 Hz, 1H), 8.17 (dd, J=8.6,1.5 Hz, 1H), 8.06 (dd, J=8.6, 4.3 Hz, 1H), 7.99-7.88 (m, 1H), 7.66 (dd,J=7.8, 1.7 Hz, 1H), 7.62-7.49 (m, 2H), 7.48-7.36 (m, 3H), 7.29 (d, J=7.5Hz, 1H), 4.39 (s, 2H), 4.09 (s, 3H), 3.44-3.66 (m, 4H), 2.66 (s, 3H),2.12 (s, 3H), 1.90-1.77 (m, 4H), 1.29 (s, 3H). MS: (ES) m/z calculatedfor C₃₄H₃₆ClN₆O₂ [M+H]⁺ 595.3, found 595.5.

Example 45:(3R,4R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride using aprocedure similar to step e in Example 1. The crude material waspurified by silica gel chromatography to give the product(3R,4R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol.¹H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.2, 1.5 Hz, 1H), 8.10-8.00 (m,2H), 7.86-7.72 (m, 2H), 7.61 (dd, J=7.7, 1.7 Hz, 1H), 7.48 (dd, J=7.6Hz, 1H), 7.42-7.32 (m, 2H), 7.25 (d, J=7.4 Hz, 1H), 7.15-7.08 (m, 1H),4.02 (s, 3H), 3.96-3.82 (m, 5H), 3.54-3.38 (m, 2H), 2.88 (d, J=10.9 Hz,1H), 2.58 (s, 3H), 2.16 (s, 3H), 1.92-1.78 (m, 1H), 1.71 (d, J=13.2 Hz,1H). MS: (ES) m/z calculated for C₃₃H₃₄ClN₆O₃ [M+H]⁺ 597.2, found 597.6.

Example 46:2-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,5,7-triazaspiro[3.4]octan-6-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 2,5,7-triazaspiro[3.4]octan-6-one hydrochloride using a proceduresimilar to step e in Example 1. The product was purified by preparativeHPLC to give the desired product2-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,5,7-triazaspiro[3.4]octan-6-one.¹H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.88 (dd, J=4.3, 1.5 Hz, 1H),8.14 (dd, J=8.5, 1.5 Hz, 1H), 7.93-7.87 (m, 2H), 7.65 (dd, J=7.7, 1.8Hz, 1H), 7.56 (dd, J=7.6, 7.6 Hz, 1H), 7.42-7.33 (m, 3H), 7.13 (dd,J=7.6, 1.3 Hz, 1H), 7.00 (s, 1H), 3.95 (s, 3H), 3.62-3.50 (m, 8H), 2.50(s, 3H), 2.08 (s, 3H). MS: (ES) m/z calculated for C₃₃H₃₂ClN₈O₂ [M+H]⁺607.2, found 607.2.

Example47:1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 3-methylazetidine-3-carboxylic acid using a procedure similar toExample 1. The crude product was purified by preparative HPLC to give1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 9.06 (dd, J=4.4, 1.4 Hz, 1H), 8.26 (dd,J=8.6, 1.4 Hz, 1H), 8.07 (dd, J=8.6, 4.4 Hz, 1H), 8.03-7.93 (m, 2H),7.64 (dd, J=7.7, 1.7 Hz, 1H), 7.62-7.57 (m, 1H), 7.53 (dd, J=7.6, 7.6Hz, 1H), 7.49-7.42 (m, 1H), 7.42-7.37 (m, 1H), 7.35 (d, J=7.5 Hz, 1H),7.27 (dd, J=7.8, 1.3 Hz, 1H), 4.63-4.43 (m, 4H), 4.18 (dd, J=16.9, 11.5Hz, 2H), 4.07 (s, 3H), 2.68 (s, 3H), 2.10 (s, 3H), 1.63 (s, 3H). MS:(ES) m/z calculated for C₃₃H₃₂ClN₆O₃ [M+H]⁺ 595.2, found 595.5.

Example 48:3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropanamide

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 3-amino-2,2-dimethylpropanamide using a procedure similar to step ein Example 1. The product was purified by preparative HPLC to give thedesired product3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropanamide.¹H NMR (400 MHz, CD₃OD) δ 9.06 (dd, J=4.3, 1.4 Hz, 1H), 8.17 (dd, J=8.6,1.4 Hz, 1H), 8.06 (dd, J=8.6, 4.4 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H),7.68-7.51 (m, 3H), 7.48-7.29 (m, 4H), 4.29 (s, 2H), 4.12 (s, 3H), 3.14(s, 2H), 2.66 (s, 3H), 2.12 (s, 3H), 1.35 (s, 6H). MS: (ES) m/zcalculated for C₃₃H₃₄ClN₇O₂ [M+H]⁺ 596.3, found 596.5.

Example 49:(S)-5-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)piperidin-2-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-5-aminopiperidin-2-one hydrochloride using a procedure similarto step e in Example 1. The product was purified by preparative HPLC togive the desired product(S)-5-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)piperidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.3, 1.5 Hz, 1H), 8.05 (ddd,J=8.1, 5.3, 1.4 Hz, 2H), 7.83-7.74 (m, 2H), 7.61 (dd, J=7.7, 1.7 Hz,1H), 7.50-7.34 (m, 3H), 7.24 (d, J=7.5 Hz, 1H), 7.12 (dd, J=7.6, 1.3 Hz,1H), 4.02 (s, 3H), 3.90-3.81 (m, 2H), 3.49 (ddd, J=12.1, 4.6, 1.5 Hz,1H), 3.13 (dd, J=12.2, 7.6 Hz, 1H), 3.04-2.98 (m, 1H), 2.58 (s, 3H),2.50-2.29 (m, 2H), 2.16 (s, 3H), 2.16-2.04 (m, 1H), 1.83-1.73 (m, 1H).MS: (ES) m/z calculated for C₃₃H₃₃ClN₇O₂ [M+H]⁺ 594.2, found 594.6.

Example 50:(R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (R)-4-aminopyrrolidin-2-one hydrochloride using a procedure similarto step e in Example 1. The product was purified by preparative HPLC togive the desired product(R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.2, 1.5 Hz, 1H), 8.06 (ddd,J=8.2, 6.0, 1.4 Hz, 2H), 7.83-7.73 (m, 2H), 7.61 (dd, J=7.6, 1.7 Hz,1H), 7.48 (dd, J=7.6, 7.6 Hz, 1H), 7.39-7.35 (m, 2H), 7.25 (d, J=7.4 Hz,1H), 7.13-7.11 (m, 1H), 4.02 (s, 3H), 3.82 (d, J=2.3 Hz, 2H), 3.69-3.60(m, 2H), 3.27-3.24 (m, 1H), 2.64-2.60 (m, 1H), 2.58 (s, 3H), 2.30-2.24(m, 1H), 2.16 (s, 3H). MS: (ES) m/z calculated for C₃₂H₃₁ClN₇O₂ [M+H]⁺580.2, found 580.5.

Example 51:(R)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (R)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a proceduresimilar to step e in Example 1. The product was purified by preparativeHPLC to give the desired product(R)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 8.85 (dd, J=4.3, 1.5 Hz, 1H), 8.06 (ddd,J=11.5, 8.3, 1.4 Hz, 2H), 7.83 (dd, J=8.5, 4.3 Hz, 1H), 7.74 (d, J=7.5Hz, 1H), 7.61 (dd, J=7.6, 1.8 Hz, 1H), 7.49 (dd, J=7.6, 7.6 Hz, 1H),7.40-7.32 (m, 2H), 7.25 (d, J=7.4 Hz, 1H), 7.13 (dd, J=7.6, 1.2 Hz, 1H),4.03 (s, 3H), 3.86 (s, 3H), 2.78-2.68 (m, 2H), 2.59 (s, 3H), 2.37-2.13(m, 6H), 1.85-1.75 (m, 1H). MS. (ES) m/z calculated for C₃₃H₃₃ClN₇O₂[M+H]⁺ 594.2, found 594.5.

Example 52:N-(2′-chloro-3′-(5-((isopropylamino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand propan-2-amine using a procedure similar to step e in Example 1. Theproduct was purified by preparative HPLC to give the desired productN-(2′-chloro-3′-(5-((isopropylamino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine.¹H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.3, 1.5 Hz, 1H), 8.06 (ddd,J=8.2, 3.1, 1.4 Hz, 2H), 7.81 (dd, J=8.5, 4.2 Hz, 1H), 7.73 (d, J=7.5Hz, 1H), 7.61 (dd, J=7.7, 1.8 Hz, 1H), 7.47 (dd, J=7.6, 7.6 Hz, 1H),7.41-7.32 (m, 2H), 7.25 (d, J=7.4 Hz, 1H), 7.11 (dd, J=7.6, 1.2 Hz, 1H),4.03 (s, 3H), 3.84 (s, 2H), 2.91 (sep, J=6.3 Hz, 1H), 2.58 (s, 3H), 2.16(s, 3H), 1.16 (d, J=6.3 Hz, 6H). MS: (ES) m/z calculated for C₃₁H₃₂ClN₆O[M+H]⁺ 539.2, found 539.2.

Example 53:2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-methylpropanoicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 2-amino-2-methylpropanoic acid using a procedure similar to step ein Example 1. The product was purified by preparative HPLC to give thedesired product2-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-methylpropanoicacid. ¹H NMR (400 MHz, CD₃OD) δ 9.05 (dd, J=4.4, 1.5 Hz, 1H), 8.17 (dd,J=8.6, 1.4 Hz, 1H), 8.06 (dd, J=8.6, 4.3 Hz, 1H), 7.91 (d, J=7.6 Hz,1H), 7.65-7.48 (m, 3H), 7.46-7.28 (m, 4H), 4.29 (s, 2H), 4.09 (s, 3H),2.66 (s, 3H), 2.13 (s, 3H), 1.70 (s, 6H). MS: (ES) m/z calculated forC₃₂H₃₂ClN₆O₃ [M+H]⁺ 583.2, found 583.2.

Example 54:((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)glycine

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand glycine using a procedure similar to step e in Example 1. Theproduct was purified by preparative HPLC to give the desired product((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)glycine.¹H NMR (400 MHz, CD₃OD) δ 9.06 (dd, J=4.4, 1.4 Hz, 1H), 8.18 (dd, J=8.6,1.4 Hz, 1H), 8.06 (dd, J=8.6, 4.3 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H),7.67-7.48 (m, 3H), 7.46-7.28 (m, 4H), 4.35 (s, 2H), 4.09 (s, 3H), 3.96(s, 2H), 2.66 (s, 3H), 2.12 (s, 3H). MS: (ES) m/z calculated forC₃H₂₈ClN₆O₃ [M+H]+ 555.2, found 555.2.

Example 55:N-(2′-chloro-3′-(5-((dimethylamino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand dimethylamine using a procedure similar to step e in Example 1. Theproduct was purified by preparative HPLC to give the desired productN-(2′-chloro-3′-(5-((dimethylamino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine.¹H NMR (400 MHz, CD₃OD) δ 8.83 (dd, J=4.3, 1.5 Hz, 1H), 8.06 (ddd,J=8.3, 8.3, 1.4 Hz, 2H), 7.82 (dd, J=8.5, 4.2 Hz, 1H), 7.72 (d, J=7.5Hz, 1H), 7.63 (dd, J=7.7, 1.8 Hz, 1H), 7.49 (dd, J=7.6, 7.6 Hz, 1H),7.43-7.33 (m, 2H), 7.26 (d, J=7.5 Hz, 1H), 7.12 (dd, J=7.5, 1.3 Hz, 1H),4.00 (s, 3H), 3.61 (s, 2H), 2.59 (s, 3H), 2.34 (s, 6H), 2.16 (s, 3H).MS: (ES) m/z calculated for C₃₀H₃₀ClN₆O [M+H]⁺ 525.2, found 525.2.

Example56:1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidin-4-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand piperidin-4-ol using a procedure similar to step e in Example 1. Theproduct was purified by preparative HPLC to give the desired product1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidin-4-ol.¹H NMR (400 MHz, CD₃OD) δ 8.83 (dd, J=4.3, 1.5 Hz, 1H), 8.06 (ddd,J=9.5, 8.2, 1.4 Hz, 2H), 7.86-7.72 (m, 2H), 7.62 (dd, J=7.6, 1.7 Hz,1H), 7.48 (dd, J=7.6, 7.6 Hz, 1H), 7.42-7.31 (m, 2H), 7.27 (d, J=7.5 Hz,1H), 7.13 (dd, J=7.6, 1.2 Hz, 1H), 4.00 (s, 3H), 3.67 (s, 3H), 2.95-2.91(m, 2H), 2.59 (s, 3H), 2.42-2.34 (m, 2H), 2.16 (s, 3H), 1.92-1.87 (m,2H), 1.67-1.58 (m, 2H). MS: (ES) m/z calculated for C₃₃H₃₄ClN₆O₂ [M+H]⁺581.2, found 581.2.

Example 57:(3S,4S)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (3S,4S)-4-aminotetrahydro-2H-pyran-3-ol using a procedure similar tostep e in Example 1. The product was purified by preparative HPLC togive the desired product(3S,4S)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol.¹H NMR (400 MHz, CD₃OD) δ 8.83 (dd, J=4.3, 1.5 Hz, 1H), 8.06 (ddd,J=12.0, 8.3, 1.4 Hz, 2H), 7.86-7.76 (m, 2H), 7.62 (dd, J=7.7, 1.8 Hz,1H), 7.49 (dd, J=7.6, 7.6 Hz, 1H), 7.42-7.33 (m, 2H), 7.29 (d, J=7.4 Hz,1H), 7.13 (dd, J=7.7, 1.2 Hz, 1H), 4.09-3.87 (m, 8H), 3.56-3.39 (m, 1H),3.08 (d, J=11.2 Hz, 1H), 2.59 (s, 3H), 2.16 (s, 3H), 1.98-1.88 (m, 1H),1.77 (d, J=12.2 Hz, 1H), 1.29 (t, J=7.3 Hz, 1H). MS: (ES) m/z calculatedfor C₃₃H₃₄ClN₆O₃ [M+H]⁺ 597.2, found 597.6.

Example 58:(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methylpyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methylnicotinaldehydeand (S)-5-(aminomethyl)pyrrolidin-2-one using a procedure similar tostep e in Example 1. The product was purified by preparative HPLC togive the desired product(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methylpyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 8.84 (dd, J=4.3, 1.5 Hz, 1H), 8.07 (ddd,J=16.4, 8.3, 1.4 Hz, 2H), 7.92-7.78 (m, 2H), 7.56-7.33 (m, 5H), 7.12(dd, J=7.5, 1.2 Hz, 1H), 4.02-3.82 (m, 2H), 3.24-3.19 (m, 1H), 2.89-2.78(m, 2H), 2.64 (s, 3H), 2.58 (s, 3H), 2.40-2.22 (m, 3H), 2.17 (s, 3H),1.93-1.84 (m, 1H). MS: (ES) m/z calculated for C₃₃H₃₃ClN₇O [M+H]⁺ 578.2,found 578.5.

Example59:1-((6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol

The compound was prepared from6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand azetidin-3-ol using a procedure similar to step e in Example 1. Theproduct was purified by preparative HPLC to give the desired product1-((6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol.¹H NMR (400 MHz, CD₃OD) δ 9.14 (d, J=1.8 Hz, 1H), 8.96 (d, J=1.9 Hz,1H), 8.69-8.62 (m, 1H), 8.21 (d, J=6.4 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H),7.68 (dd, J=7.8, 1.9 Hz, 1H), 7.57-7.52 (m, 2H), 7.48-7.34 (m, 3H),7.28-7.20 (m, 1H), 4.78-4.60 (m, 1H), 4.49-4.39 (m, 4H), 4.11-3.98 (m,5H). MS: (ES) m/z calculated for C₂₉H₂₅Cl₂N₆O₂ [M+H]⁺ 559.1, found559.1.

Example 60:(S)-4-(((6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one

The compound was prepared from6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-4-aminopyrrolidin-2-one using a procedure similar to step e inExample 1. The product was purified by preparative HPLC to give thedesired product(S)-4-(((6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one.¹HNMR (400 MHz, CD₃OD) δ 9.10 (s, 1H), 8.93 (s, 1H), 8.86 (d, J=8.3 Hz,1H), 8.30 (d, J=6.4 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.70-7.63 (m, 1H),7.58-7.35 (m, 5H), 7.16 (d, J=7.6 Hz, 1H), 4.33 (s, 2H), 4.28-4.21 (m,1H), 4.12 (s, 3H), 3.91-3.83 (m, 1H), 3.61-3.57 (m, 1H), 2.95-2.87 (m,1H), 2.66-2.55 (m, 1H). MS: (ES) m/z calculated for C₃H₂₆C₂N₇O₂ [M+H]⁺586.2, found 586.1.

Example61:1-((6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylicacid

The compound was prepared from6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand azetidine-3-carboxylic acid using a procedure similar to step e inExample 1. The product was purified by preparative HPLC to give thedesired product1-((6-(2,2′-dichloro-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 9.13 (s, 1H), 8.95 (s, 1H), 8.70-8.63(m, 1H), 8.21 (d, J=6.3 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.68 (dd,J=7.7, 1.8 Hz, 1H), 7.56-7.52 (m, 2H), 7.47-7.34 (m, 3H), 7.23 (dd,J=7.7, 1.7 Hz, 1H), 4.5 (s, 2H), 4.43-4.41 (m, 4H), 4.09 (s, 3H),3.78-3.69 (m, 1H). MS: (ES) m/z calculated for C₃H₂₅Cl₂N₆O₃ [M+H]⁺587.1, found 587.1.

Example62:3-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-2-carbonitrile

The compound was prepared from3-(5-formyl-6-methoxypyridin-2-yl)-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-2-carbonitrileand (3R,4R)-4-aminotetrahydropyran-3-ol hydrochloride using a proceduresimilar to step e in Example 1. The product was purified by preparativeHPLC to give the desired product3-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-2-carbonitrile.¹HNMR (400 MHz, CDCl₃) δ 9.24 (s, 1H), 8.74 (dd, J=4.3, 1.5 Hz, 1H),8.63 (dd, J=8.4, 1.5 Hz, 1H), 8.10 (dd, J=8.4, 1.5 Hz, 1H), 7.82 (dd,J=7.9, 1.2 Hz, 1H), 7.76-7.64 (m, 3H), 7.49-7.40 (m, 2H), 7.37 (d, J=7.9Hz, 1H), 7.14 (d, J=7.9 Hz, 1H), 4.11 (s, 3H), 4.05 (dd, J=12.8, 2.8 Hz,1H), 3.98-3.77 (m, 3H), 3.43 (ddd, J=23.8, 12.0, 2.0 Hz, 2H), 2.84-2.78(m, 1H), 2.74 (s, 3H), 2.34 (s, 3H), 1.89-1.75 (m, 1H), 1.70-1.50 (m,2H). MS: (ES) m/z calculated for C₃₄H₃₄N₇O₃ [M+H]⁺ 588.3, found 588.2.

Example 63:(S)-5-((((6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-5-(aminomethyl)pyrrolidin-2-one using a procedure similar tostep e in Example 1. The crude product was purified by preparative HPLCto give(S)-5-((((6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 9.01 (s, 1H), 8.85 (s, 1H), 8.14 (d, J=6.2 Hz,1H), 8.04 (d, J=8.4 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.59 (d, J=8.0 Hz,1H), 7.46 (dd, J=7.7, 7.7 Hz, 1H), 7.39-7.32 (m, 2H), 7.25-7.19 (m, 2H),7.07 (d, J=7.4 Hz, 1H), 4.01 (s, 3H), 3.87-3.77 (m, 3H), 2.77-2.61 (m,2H), 2.36-2.20 (m, 3H), 2.15 (s, 3H), 1.85-1.75 (s, 1H). MS: (ES) m/zcalculated for C₃₂H₃₁ClN₇O₂ [M+H]⁺ 580.2, found 580.5.

Example 64:(3R,4R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-ethylnicotinaldehydeand (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride using aprocedure similar to step e in Example 1. The product was purified bypreparative HPLC to give the desired product(3R,4R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol.¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.77 (dd, J=4.2, 1.5 Hz, 1H),8.50 (d, J=7.9 Hz, 1H), 8.18 (dd, J=8.5, 1.5 Hz, 1H), 7.80 (d, J=7.9 Hz,1H), 7.72 (dd, J=8.5, 4.0 Hz, 1H), 7.61 (dd, J=7.7, 1.8 Hz, 1H), 7.53(d, J=8.0 Hz, 1H), 7.46-7.36 (m, 2H), 7.31 (dd, J=7.6, 1.8 Hz, 1H), 7.09(d, J=7.6 Hz, 1H), 4.17-3.89 (m, 4H), 3.55-3.39 (m, 2H), 3.12-3.00 (m,2H), 2.96 (q, J=7.2 Hz, 2H), 2.75 (s, 3H), 2.25 (s, 3H), 1.95-1.85 (m,1H), 1.80-1.73 (m, 1H), 1.36 (t, J=7.3 Hz, 3H). MS: (ES) m/z calculatedfor C₃₄H₃₆ClN₆O₂ [M+H]⁺ 595.3, found 595.2.

Example 65:(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-ethylnicotinaldehydeand (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a proceduresimilar to step e in Example 1. The product was purified by preparativeHPLC to give the desired product(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.74 (dd, J=4.3, 1.5 Hz, 1H),8.57 (d, J=8.2 Hz, 1H), 8.11 (dd, J=8.5, 1.5 Hz, 1H), 7.76-7.65 (m, 2H),7.61 (dd, J=7.7, 1.8 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.45-7.36 (m, 2H),7.30 (dd, J=7.5, 1.8 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.35 (s, 1H), 3.95(m, 2H), 3.83 (bs, 1H), 3.09 (q, J=7.3 Hz, 2H), 2.99-2.88 (m, 2H), 2.73(s, 3H), 2.42-2.30 (m, 2H), 2.25 (s, 3H), 2.04 (d, 1H), 1.83 (m, 1H),1.36 (t, J=7.3 Hz, 3H). MS: (ES) m/z calculated for C₃₄H₃₅ClN₇O [M+H]⁺592.3, found 592.2.

Example 66:3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-methylbutan-1-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 3-amino-3-methylbutan-1-ol using a procedure similar to step e inExample 1. The product was purified by preparative HPLC to give thedesired product3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-methylbutan-1-ol.¹H NMR (400 MHz, CD₃OD) δ 9.06 (dd, J=4.4, 1.5 Hz, 1H), 8.17 (dd, J=8.7,1.5 Hz, 1H), 8.06 (dd, J=8.6, 4.3 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H),7.66-7.48 (m, 3H), 7.48-7.25 (m, 4H), 4.26 (s, 2H), 4.07 (s, 3H), 3.92(t, J=5.8 Hz, 2H), 2.66 (s, 3H), 2.12 (s, 3H), 1.96 (t, J=5.8 Hz, 2H),1.53 (s, 6H), 1.38 (d, J=4.2 Hz, 1H). MS: (ES) m/z calculated forC₃₃H₃₆ClN₆O₂ [M+H]⁺ 583.3, found 583.5.

Example 67:3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropan-1-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 3-amino-2,2-dimethylpropan-1-ol using a procedure similar to step ein Example 1. The product was purified by preparative HPLC to give thedesired product3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropan-1-ol.¹H MMR (400 MHz, CD₃OD) δ 9.06 (dd, J=4.4, 1.4 Hz, 1H), 8.18 (dd, J=8.6,1.5 Hz, 1H), 8.06 (dd, J=8.6, 4.4 Hz, 1H), 7.86 (d, J=7.5 Hz, 1H),7.68-7.49 (m, 3H), 7.48-7.25 (m, 4H), 4.26 (s, 2H), 4.08 (s, 3H), 3.48(s, 2H), 3.09 (s, 2H), 2.66 (s, 3H), 2.12 (s, 3H), 1.02 (s, 6H). MS:(ES) m/z calculated for C₃₃H₃₆ClN₆O₂ [M+H]⁺ 583.3, found 583.5.

Example 68:1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand azetidin-3-ol using a procedure similar to step e in Example 1. Theproduct was purified by preparative HPLC to give the desired product1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol.¹H NMR (400 MHz, CD₃OD) δ 9.04 (dd, J=4.3, 1.4 Hz, 1H), 8.16 (dd, J=8.6,1.4 Hz, 1H), 8.04 (dd, J=8.6, 4.3 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H),7.68-7.58 (m, 2H), 7.53 (dd, J=7.6 Hz, 1H), 7.46-7.39 (m, 2H), 7.36 (d,J=7.5 Hz, 1H), 7.27 (d, J=7.5 Hz, 1H), 4.63 (b, 1H), 4.49 (s, 2H), 4.41(bs, 2H), 4.08 (s, 3H), 4.03 (b, 2H), 2.65 (s, 3H), 2.12 (s, 3H). MS:(ES) m/z calculated for C₃₁H₃₀ClN₆O₂ [M+H]⁺ 553.2, found 553.5.

Example 69:(S)—N-(2′-chloro-3′-(6-methoxy-5-(((tetrahydrofuran-3-yl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-tetrahydrofuran-3-amine using a procedure similar to step e inExample 1. The product was purified by preparative HPLC to give thedesired product(S)—N-(2′-chloro-3′-(6-methoxy-5-(((tetrahydrofuran-3-yl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1′-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine.¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 1H), 8.73 (dd, J=4.3, 1.5 Hz, 1H),8.58 (dd, J=8.2, 1.3 Hz, 1H), 8.11 (dd, J=8.5, 1.5 Hz, 1H), 7.73-7.59(m, 3H), 7.41 (dd, J=7.8 Hz, 2H), 7.33-7.24 (m, 2H), 7.06 (dd, J=7.8,1.3 Hz, 1H), 4.04 (s, 3H), 3.98 (m, 1H), 3.90-3.78 (m, 4H), 3.71 (dd,J=9.6, 3.6 Hz 1H), 3.55-3.45 (m, 1H), 2.73 (s, 3H), 2.27 (s, 3H),2.22-2.09 (m, 1H), 1.90-1.80 (m, 1H). MS: (ES) m/z calculated forC₃₂H₃₂ClN₆O₂ [M+H]⁺ 567.2, found 567.5.

Example 70:3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropanoicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 3-amino-2,2-dimethylpropanoic acid using a procedure similar to stepe in Example 1. The product was purified by preparative HPLC to give thedesired product3-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropanoicacid. ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.73 (dd, J=4.1, 1.5 Hz,1H), 8.58 (d, J=8.3 Hz, 1H), 8.10 (dd, J=8.4, 1.5 Hz, 1H), 7.73-7.60 (m,3H), 7.46-7.36 (m, 2H), 7.32-7.28 (m, 2H), 7.06 (d, J=7.6 Hz, 1H), 4.10(s, 3H), 4.00 (s, 2H), 2.75 (s, 2H), 2.73 (s, 3H), 2.26 (s, 3H), 2.06(s, 1H), 1.23 (s, 6H). MS: (ES) m/z calculated for C₃₃H₃₄ClN₆O₃ [M+H]⁺597.2, found 597.5.

Example 71:1-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-methylpropan-2-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 1-amino-2-methylpropan-2-ol using a procedure similar to step e inExample 1. The product was purified by preparative HPLC to give thedesired product1-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-methylpropan-2-ol.¹H NMR (400 MHz, CD₃OD) δ 9.05 (dd, J=4.3, 1.4 Hz, 1H), 8.17 (dd, J=8.6,1.4 Hz, 1H), 8.06 (dd, J=8.6, 4.4 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.66(dd, J=7.6, 1.4 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.53 (dd, J=7.6 Hz,1H), 7.46-7.38 (m, 2H), 7.37 (d, J=7.6 Hz, 1H), 7.28 (dd, J=7.6, 1.4 Hz,1H), 4.34 (s, 2H), 4.09 (s, 3H), 3.03 (s, 2H), 2.66 (s, 3H), 2.12 (s,3H), 1.31 (s, 6H). MS: (ES) m/z calculated for C₃₂H₃₄ClN₆O₂ [M+H]⁺569.2, found 569.5.

Example 72:(R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (R)-4-amino-3-hydroxybutanoic acid using a procedure similar to stepe in Example 1. The crude product was purified by preparative HPLC togive(R)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoicacid. ¹H NMR (400 MHz, CD₃OD) δ 9.03 (dd, J=4.4, 1.4 Hz, 1H), 8.15 (dd,J=8.6, 1.4 Hz, 1H), 8.03 (dd, J=8.6, 4.3 Hz, 1H), 7.88 (d, J=7.5 Hz,1H), 7.64 (ddd, J=7.7, 1.9, 1.9 Hz, 2H), 7.53 (dd, J=7.6, 7.6 Hz, 1H),7.48-7.38 (m, 2H), 7.35 (d, J=7.5 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H),4.37-4.31 (m, 3H), 4.09 (s, 3H), 3.30-3.26 (m, 1H), 3.07 (dd, J=12.7,9.8 Hz, 1H), 2.65 (s, 3H), 2.57 (d, J=6.3 Hz, 2H), 2.12 (s, 3H). MS:(ES) m/z calculated for C₃₂H₃₂ClN₆O₄ [M+H]⁺ 599.2, found 599.4.

Example 73:(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-(trifluoromethyl)pyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-(trifluoromethyl)nicotinaldehydeand (S)-5-(aminomethyl)pyrrolidin-2-one using a procedure similar tostep e in Example 1. The crude product was purified by preparative HPLCto give(S)-5-((((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-(trifluoromethyl)pyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 8.83 (dd, J=4.3, 1.5 Hz, 1H), 8.30 (d, J=8.2Hz, 1H), 8.06 (ddd, J=9.5, 8.3, 1.4 Hz, 2H), 7.94 (d, J=8.2 Hz, 1H),7.82 (dd, J=8.5, 4.3 Hz, 1H), 7.61 (dd, J=7.7, 1.8 Hz, 1H), 7.53 (dd,J=7.6, 7.6 Hz, 1H), 7.44 (dd, J=7.5, 1.8 Hz, 1H), 7.39 (dd, J=7.9, 7.9Hz, 1H), 7.14 (dd, J=7.7, 1.3 Hz, 1H), 4.06 (s, 2H), 3.88-3.79 (m, 1H),2.83-2.62 (m, 2H), 2.58 (s, 3H), 2.42-2.21 (m, 3H), 2.17 (s, 3H),1.91-1.80 (m, 1H). MS. (ES) m/z calculated for C₃₃H₃₀C₁F₃N₇₀ [M+H]+632.2, found 632.5.

Example 74:(R)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidine-3-carboxylicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (R)-piperidine-3-carboxylic acid using a procedure similar to step ein Example 1. The crude product was purified by preparative HPLC to give(R)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidine-3-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 8.83 (dd, J=4.2, 1.5 Hz, 1H), 8.07 (dd,J=8.5, 1.5 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.82(dd, J=8.5, 4.3 Hz, 1H), 7.66 (dd, J=7.6, 1.6 Hz), 7.51 (dd, J=7.6, 7.6Hz, 1H), 7.43-7.33 (m, 3H), 7.12 (dd, J=7.5, 1.3 Hz, 1H), 4.25 (t,J=13.7 Hz, 2H), 4.10 (s, 3H), 3.30-3.24 (m, 1H), 3.17-3.04 (m, 3H), 2.70(bs, 1H), 2.58 (s, 3H), 2.16 (s, 3H), 2.08-1.74 (m, 3H), 1.28 (t, J=7.3Hz, 1H). MS: (ES) m/z calculated for C₃₄H₃₄ClN₆O₃ [M+H]⁺ 609.2, found609.6.

Example 75:(S)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-4-amino-3-hydroxybutanoic acid using a procedure similar to stepe in Example 1. The crude product was purified by preparative HPLC togive(S)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoicacid. ¹H NMR (400 MHz, CD₃OD) δ 8.74 (dd, J=16.8, 4.4 Hz, 1H), 8.11-7.94(m, 2H), 7.82-7.66 (m, 2H), 7.54 (dt, J=7.7, 2.3 Hz, 1H), 7.38 (ddd,J=7.6, 7.6, 1.6 Hz, 1H), 7.35-7.24 (m, 2H), 7.12 (dd, J=7.6, 1.5 Hz,1H), 7.03 (dd, J=7.6, 3.0 Hz, 1H), 4.62 (bs, 2H), 4.30 (bs, 1H), 3.96(s, 3H), 4.08-3.72 (m, 2H), 3.34 (s, 3H), 2.82 (m, 1H), 2.53 (s, 3H),2.52-2.28 (m, 1H). MS: (ES) m/z calculated for C₃₂H₃₂ClN₆O₄ [M+H]⁺599.2, found 599.5.

Example 76:(S)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidine-2-carboxylicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-piperidine-2-carboxylic acid using a procedure similar to step ein Example 1. The crude product was purified by preparative HPLC to give(S)-1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidine-2-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.3, 1.5 Hz, 1H), 8.06 (dd,J=8.8, 1.6 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.81(dd, J=8.5, 4.2 Hz, 1H), 7.63 (dd, J=7.7, 1.7 Hz, 1H), 7.49 (dd, J=7.6,7.6 Hz, 1H), 7.43-7.33 (m, 3H), 7.11 (d, J=7.6 Hz, 1H), 4.51-4.15 (m,2H), 4.04 (s, 3H), 3.48-3.33 (m, 2H), 2.88 (bs, 1H), 2.58 (s, 3H),2.25-2.16 (m, 1H), 2.15 (s, 3H), 1.93-1.63 (m, 4H), 1.58-1.45 (m, 1H).MS: (ES) m/z calculated for C₃₄H₃₄ClN₆O₃ [M+H]⁺ 609.2, found 609.6.

Example77:2-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-5-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (2,6-diazaspiro[3.4]octan-5-one using a procedure similar to step ein Example 1. The crude product was purified by preparative HPLC to give2-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-5-one.¹H NMR (400 MHz, CD₃OD) δ 8.82 (dd, J=4.3, 1.5 Hz, 1H), 8.05 (ddd,J=7.9, 6.5, 1.4 Hz, 2H), 7.81 (dd, J=8.4, 4.3 Hz, 1H), 7.68 (d, J=7.5Hz, 1H), 7.59 (dd, J=7.7, 1.7 Hz, 1H), 7.47 (dd, J=7.6, 7.6 Hz, 1H),7.43-7.31 (m, 2H), 7.22 (d, J=7.5 Hz, 1H), 7.11 (dd, J=7.6, 1.3 Hz, 1H),3.99 (s, 3H), 3.73 (s, 2H), 3.53 (d, J=8.8 Hz, 2H), 3.40 (d, J=8.4 Hz,2H), 3.34 (s, 2H), 2.58 (s, 3H), 2.49 (t, J=6.8 Hz, 2H), 2.15 (s, 3H).MS: (ES) m/z calculated for C₃₄H₃₃ClN₇O₂ [M+H]+ 606.2, found 606.5.

Example 78:2-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,5-diazaspiro[3.4]octan-6-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand 2,5-diazaspiro[3.4]octan-6-one using a procedure similar to step ein Example 1. The crude product was purified by preparative HPLC to give2-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,5-diazaspiro[3.4]octan-6-one.¹H NMR (400 MHz, CD₃OD) δ 9.06 (dd, J=4.3, 1.4 Hz, 1H), 8.17 (dd, J=8.6,1.5 Hz, 1H), 8.06 (dd, J=8.6, 4.4 Hz, 1H), 7.92 (dd, J=7.3, 7.3 Hz, 1H),7.64 (dd, J=7.7, 1.9 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.53 (dd, J=6.8Hz, 1H), 7.48-7.37 (m, 2H), 7.37 (dd, J=7.6, 2.0 Hz, 1H), 7.28 (d, J=7.7Hz, 1H), 4.66-4.44 (m, 3H), 4.39-4.23 (m, 3H), 4.09 (s, 3H), 3.37-3.32(m, 2H), 2.66 (s, 3H), 2.54 (t, J=6.8 Hz, 2H), 2.11 (s, 3H). MS: (ES)m/z calculated for C₃₄H₃₃ClN₇O₂ [M+H]⁺ 606.2, found 606.5.

Example 79:(R)-5-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)piperidin-2-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (R)-5-aminopiperidin-2-one using a procedure similar to step e inExample 1. The crude product was purified by preparative HPLC to give(R)-5-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)piperidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 9.05 (dd, J=4.4, 1.4 Hz, 1H), 8.17 (dd, J=8.6,1.5 Hz, 1H), 8.05 (dd, J=8.6, 4.3 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.64(dd, J=7.7, 1.8 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.53 (dd, J=7.7, 7.7Hz, 1H), 7.47-7.39 (m, 2H), 7.37 (d, J=7.5 Hz, 1H), 7.28 (d, J=8.8 Hz,1H), 4.40 (d, J=12.8 Hz, 1H), 4.35 (d, J=13.2 Hz, 1H), 4.10 (s, 3H),3.81-3.73 (m, 2H), 3.53-3.46 (m, 1H), 2.66 (s, 3H), 2.52 (d, J=6.4, Hz,1H), 2.50 (d, J=6.0 Hz, 1H), 2.43-2.35 (bs, 1H), 2.16-2.06 (m, 1H) 2.12(s, 3H). MS: (ES) m/z calculated for C₃₃H₃₃ClN₇O₂ [M+H]⁺ 594.2, found594.5.

Example 80:(S)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (S)-4-aminopyrrolidin-2-one using a procedure similar to step e inExample 1. The crude product was purified by preparative HPLC to give(S)-4-(((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one.¹H NMR (400 MHz, CD₃OD) δ 9.06 (dd, J=4.3, 1.4 Hz, 1H), 8.18 (dd, J=8.6,1.5 Hz, 1H), 8.06 (dd, J=8.6, 4.4 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.64(dd, J=7.7, 1.7 Hz, 1H), 7.58 (dd, J=8.0, 1.2 Hz, 1H), 7.53 (dd, J=7.6,7.6 Hz, 1H), 7.48-7.39 (m, 2H), 7.37 (d, J=7.5 Hz, 1H), 7.28 (dd, J=7.7,1.3 Hz, 1H), 4.33 (s, 2H), 4.24 (dq, J=8.4, 4.2 Hz, 1H), 4.10 (s, 3H),3.88 (dd, J=11.6, 7.6 Hz, 1H), 3.61 (dd, J=11.6, 4.0 Hz, 1H), 2.91 (dd,J=17.7, 8.8 Hz, 1H), 2.66 (s, 3H), 2.59 (dd, J=17.7, 4.7 Hz, 1H), 2.12(s, 3H). MS: (ES) m/z calculated for C₃₂H₃₁ClN₇O₂ [M+H]⁺ 580.2, found580.5.

Example81:1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand azetidine-3-carboxylic acid using a procedure similar to step e inExample 1. The crude product was purified by preparative HPLC to give1-((6-(2-chloro-2′-methyl-3′-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 9.05 (dd, J=4.4, 1.4 Hz, 1H), 8.19 (dd,J=8.6, 1.4 Hz, 1H), 8.05 (dd, J=8.6, 4.4 Hz, 1H), 7.89 (d, J=7.5 Hz,1H), 7.64 (dd, J=7.8, 1.7 Hz, 1H), 7.59 (dd, J=8.0, 1.3 Hz, 1H), 7.53(ddd, J=7.6, 7.6, 3.4 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.40 (ddd, J=7.6,2.9, 1.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.7 Hz, 1H),4.60-4.30 (m, 4H), 4.08 (s, 3H), 3.74 (p, J=8.6 Hz, 1H), 2.92 (s, 2H),2.66 (s, 3H), 2.11 (s, 3H). MS: (ES) m/z calculated for C₃₂H₂₉ClN₆O₃[M+H]⁺ 581.2, found 581.5.

Example 82:(3R,4R)-4-(((6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol using a procedure similar tostep e in Example 1. The crude product was purified by preparative HPLCto give(3R,4R)-4-(((6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol.¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 9.11 (s, 1H), 8.93 (s, 1H),8.22 (d, J=5.9 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H),7.61 (d, J=7.1 Hz, 1H), 7.51 (dd, J=7.7, 7.7 Hz, 1H), 7.40-7.29 (m, 2H),7.29-7.19 (m, 2H), 7.01 (d, J=7.6 Hz, 1H), 4.63 (bs, 1H), 3.90 (s, 3H),3.79-3.58 (m, 4H), 3.36-3.25 (m, 4H), 2.67 (s, 1H), 2.09 (s, 3H), 1.65(t, J=10.2 Hz, 1H), 1.51 (d, J=13.2 Hz, 1H). MS: (ES) m/z calculated forC₃₂H₃₂ClN₆O₃ [M+H]⁺ 583.2, found 583.5.

Example83:1-((6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylicacid

The compound was prepared from6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand azetidine-3-carboxylic acid using a procedure similar to step e inExample 1. The crude product was purified by preparative HPLC to give1-((6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylicacid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 9.12 (s, 1H), 8.93 (s,1H), 8.22 (d, J=6.1 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.74-7.63 (m, 1H),7.61 (d, J=7.4 Hz, 1H), 7.51 (dd, J=7.7, 7.7 Hz, 1H), 7.40-7.29 (m, 2H),7.24 (dd, J=8.3, 6.6 Hz, 2H), 7.08-6.96 (m, 1H), 3.89 (s, 3H), 3.54 (s,2H), 3.49-3.15 (m, 6H), 2.08 (s, 3H). MS: (ES) m/z calculated forC₃₁H₂₈ClN₆O₃ [M+H]⁺ 567.2, found 567.5.

Example 84:1-((6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol

The compound was prepared from6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxynicotinaldehydeand azetidin-3-ol using a procedure similar to step e in Example 1. Thecrude product was purified by preparative HPLC to give1-((6-(2-chloro-2′-methyl-3′-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1′-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol.¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 9.11 (d, J=1.8 Hz, 1H), 8.93(d, J=1.9 Hz, 1H), 8.22 (d, J=6.0 Hz, 1H), 8.17-8.14 (d, J=8.0 Hz, 1H),7.66 (d, J=7.6 Hz, 1H), 7.61 (dd, J=7.8, 1.7 Hz, 1H), 7.50 (dd, J=7.7,7.7 Hz, 1H), 7.40-7.30 (m, 2H), 7.26-7.21 (m, 2H), 7.02 (d, J=7.2 Hz,1H), 5.31 (d, J=6.5 Hz, 1H), 4.20 (q, J=6.2 Hz, 1H), 3.89 (s, 3H),3.64-3.49 (m, 4H), 2.91-2.75 (m, 2H), 2.08 (s, 3H). MS: (ES) m/zcalculated for C₃₀H₂₈ClN₆O₂ [M+H]⁺ 539.2, found 539.4.

Biological Example: Enzyme-Linked Immunosorbent Assay—ELISA

96 Well plates were coated with 1 μg/mL of human PD-L1 (obtained fromR&D) in PBS overnight at 4° C. The wells were then blocked with 2% BSAin PBS (W/V) with 0.05% TWEEN-20 for 1 hour at 37° C. The plates werewashed 3 times with PBS/0.05% TWEEN-20 and the compounds were serialdiluted (1:5) in dilution medium and added to the ELISA plates. HumanPD-1 and biotin 0.3 μg/mL (ACRO Biosystems) were added and incubated for1 hour at 37° C. then washed 3 times with PBS/0.05% TWEEN-20. A secondblock was performed with 200BSA in PBS (W/V)/0.05%0 TWEEN-20 for 10 minat 37° C. and the plates were washed 3 times with PBS/0.05% TWEEN-20.Streptavidin-HRP was added for 1 hour at 37° C. then the plates werewashed 3 times with PBS/0.05% TWEEN-20. TMB substrate was added andreacted for 20 min at 37° C. A stop solution (2 N aqueous H₂S₄) wasadded. The absorbance was read at 450 nm using a micro-platespectrophotometer. The results are shown in Table 1: C₅₀ values areprovided as follows: from 1000 to 10,000 nM (+); from 10 up to 1000 nM(++); less than 10 nM (+++).

TABLE 1 ELISA IC50 Compound Structure (nM) 1.001

+++ 1.002

+++ 1.003

+++ 1.004

+++ 1.005

+++ 1.006

+++ 1.007

+++ 1.008

+++ 1.009

+++ 1.010

+++ 1.011

+++ 1.012

+++ 1.013

+++ 1.014

+++ 1.015

+++ 1.016

+++ 1.017

+++ 1.018

+++ 1.019

+++ 1.020

+++ 1.021

+++ 1.022

+++ 1.023

+++ 1.024

+++ 1.025

+++ 1.026

+++ 1.027

+++ 1.028

+++ 1.029

+++ 1.030

+++ 1.031

+++ 1.032

+++ 1.033

+++ 1.034

+++ 1.035

+++ 1.036

+++ 1.037

+++ 1.038

+++ 1.039

+++ 1.040

+++ 1.041

+++ 1.042

+++ 1.043

+++ 1.044

+++ 1.045

+++ 1.046

+++ 1.047

+++ 1.048

+++ 1.049

+++ 1.050

+++ 1.051

+++ 1.052

+++ 1.053

+++ 1.054

+++ 1.055

+++ 1.056

+++ 1.057

+++ 1.058

+++ 1.059

+++ 1.060

+++ 1.061

+++ 1.062

+++ 1.063

+++ 1.064

+++ 1.065

+++ 1.066

+++ 1.067

++ 1.068

+++ 1.069

+++ 1.070

+++ 1.071

+++ 1.072

+++ 1.073

+++ 1.074

+++ 1.075

+++ 1.076

+++ 1.077

+++ 1.078

+++ 1.079

+++ 1.080

+++ 1.081

+++ 1.082

+++ 1.083

+++ 1.084

+++

Particular embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Upon reading the foregoing, description, variations of the disclosedembodiments may become apparent to individuals working in the art, andit is expected that those skilled artisans may employ such variations asappropriate. Accordingly, it is intended that the invention be practicedotherwise than as specifically described herein, and that the inventionincludes all modifications and equivalents of the subject matter recitedin the claims appended hereto as permitted by applicable law. Moreover,any combination of the above-described elements in all possiblevariations thereof is encompassed by the invention unless otherwiseindicated herein or otherwise clearly contradicted by context.

All publications, patent applications, accession numbers, and otherreferences cited in this specification are herein incorporated byreference as if each individual publication or patent application werespecifically and individually indicated to be incorporated by reference.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, prodrug or bioisostere thereof,wherein: A is a 5- to 10-membered heteroaryl group which isunsubstituted or substituted with from one to five members independentlyselected from the group consisting of halogen, C₁₋₃ alkyl, C₁₋₃haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, OH, and CN; X¹ is C₁₋₃alkylene, which is unsubstituted or substituted with one or two membersindependently selected from the group consisting of C₁₋₂ alkyl and CO₂H;R^(2a) and R^(2b) are each independently selected from the groupconsisting of H, C₁₋₈ alkyl, C₁₋₈ haloalkyl, —Y, —X²—CO₂R^(a),—X²—OR^(a), —X²—NR^(a)R^(b), —X²—C(O)NR^(a)R^(b), —X²—SO₂R^(a),—X²—SO₂NR^(a)R^(b), —X²—SO₃R^(a) and —X²—Y wherein each X² is C₁₋₆alkylene and any C₁₋₈ alkyl or C₁₋₆ alkylene, is unsubstituted orsubstituted with one or two members independently selected from thegroup consisting of OH, SO₂NH₂, C(O)NH₂, C(O)NHOH, PO₃H₂, CO₂C₁₋₈alkyland CO₂H, and each Y is selected from the group consisting of C₃₋₆cycloalkyl, C₄₋₈ heterocyclyl and 5- to 6-membered heteroaryl, each ofwhich is unsubstituted or substituted with one to four substituentsindependently selected from the group consisting of oxo, OH, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄hydroxyalkoxy, SO₂NH₂, C(O)NH₂, C(O)NHOH, PO₃H₂, CO₂C₁₋₈ alkyl, SO₃H andCO₂H; or R^(2a) and R^(2b) are combined to form a 4- to 9-membered ringor spirocyclic ring, having from zero to two additional heteroatom ringvertices selected from O, N and S; wherein the ring formed by combiningR^(2a) and R^(2b), is unsubstituted or substituted with 1 to 4substituents independently selected from the group consisting of oxo,C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ hydroxyalkyl, —X³—CO₂R^(a), —X³—OR^(a),—X³—NR^(a)R^(b), —X³—C(O)NR^(a)R^(b), —X³—SO₂R^(a), —X³—SO₂NR^(a)R^(b),and —X³—SO₃R^(a); wherein X³ is a bond or C₁₋₆ alkylene; R³ and R⁴ areeach independently selected from the group consisting of H, F, Cl, CN,CH₃, OCH₃, CH₂CH₃ and CF₃; the subscript n is 0, 1, 2 or 3; each R^(3a)is independently selected from the group consisting of H, F, Cl, C₁₋₃alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₂₋₃ alkenyl andCN; R⁶, R⁷ and R⁸ are each independently selected from the groupconsisting of H, F, Cl, CN, CH₃, OCH₃, CH₂CH₃ and CF₃; Z is a fusedbicyclic heteroaryl ring, unsubstituted or substituted with one to threeR^(c); each R^(a) is independently selected from the group consisting ofH, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆alkylene-CO₂H, and C₁₋₆ alkylene-SO₃H; each R^(b) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ alkylene-CO₂H, and C₁₋₆alkylene-SO₃H, each of which is unsubstituted or substituted with one ortwo members independently selected from OH, SO₂NH₂, C(O)NH₂, C(O)NHOH,PO₃H₂, CO₂C₁₋₈ alkyl and CO₂H; and R^(a) and R^(b), when attached to thesame nitrogen atom, are optionally combined to form a 4- to 8-memberedring or spirocyclic ring, which is unsubstituted or substituted withhalogen, OH, SO₂NH₂, C(O)NH₂, C(O)NHOH, PO₃H₂, CO₂C₁₋₈ alkyl or —CO₂H;each R^(c) is independently selected from the group consisting of H,halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —Y¹, —X⁴—CO₂R^(a),—O—X⁴—CO₂R^(a), —X⁴—OR^(a), —X⁴—NR^(a)R^(b), —X⁴—C(O)NR^(a)R^(b),—O—X⁴—C(O)NR^(a)R^(b), —X⁴—SO₂R^(a), —X⁴—SO₂NR^(a)R^(b), —X⁴—SO₃R^(a),and —N(R^(a))—X⁴—CO₂R^(a), wherein each X⁴ is a bond or C₁₋₆ alkylene,and each Y¹ is selected from the group consisting of C₃₋₆ cycloalkyl andC₄₋₈ heterocyclyl; and optionally two R^(c) on adjacent ring verticesare combined to form a fused 5- or 6-membered heterocyclic ring.
 2. Acompound of Formula (I):

or a pharmaceutically acceptable salt, prodrug or bioisostere thereof,wherein: A is a 5- to 10-membered heteroaryl group which isunsubstituted or substituted with from one to five members independentlyselected from the group consisting of halogen, C₁₋₃ alkyl, C₁₋₃haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy and CN; X¹ is C₁₋₃ alkylene,which is unsubstituted or substituted with one or two membersindependently selected from the group consisting of C₁₋₂ alkyl and CO₂H;R^(2a) and R^(2b) are each independently selected from the groupconsisting of H, C₁₋₈ alkyl, C₁₋₈ haloalkyl, —Y, —X²—CO₂R^(a),—X²—OR^(a), —X²—NR^(a)R^(b), —X²—C(O)NR^(a)R^(b), —X²—SO₂R^(a),—X²—SO₂NR^(a)R^(b), —X²—SO₃R^(a) and —X²—Y wherein each X² is C₁₋₆alkylene and any C₁₋₈ alkyl or C₁₋₆ alkylene, is unsubstituted orsubstituted with one or two members independently selected from thegroup consisting of OH, SO₂NH₂, C(O)NH₂, C(O)NHOH, PO₃H₂, CO₂C₁₋₈alkyland CO₂H, and each Y is selected from the group consisting of C₃₋₆cycloalkyl, C₄₋₈ heterocyclyl and 5- to 6-membered heteroaryl, each ofwhich is unsubstituted or substituted with one to four substituentsindependently selected from the group consisting of oxo, OH, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄hydroxyalkoxy, SO₂NH₂, C(O)NH₂, C(O)NHOH, PO₃H₂, CO₂C₁₋₈ alkyl, SO₃H andCO₂H; or R^(2a) and R^(2b) are combined to form a 4- to 9-membered ringor spirocyclic ring, having from zero to two additional heteroatom ringvertices selected from O, N and S; wherein the ring formed by combiningR^(2a) and R^(2b), is unsubstituted or substituted with 1 to 4substituents independently selected from the group consisting of oxo,C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl, —X³—CO₂R^(a),—X³—OR^(a)—X³—NR^(a)R^(b), —X³—C(O)NR^(a)R^(b), —X³—SO₂R^(a),—X³—SO₂NR^(a)R^(b), and —X³—SO₃R^(a); wherein X³ is a bond or C₁₋₆alkylene; R³ and R⁴ are each independently selected from the groupconsisting of F, Cl, CN, CH₃, OCH₃, CH₂CH₃ and CF₃; the subscript n is0, 1, 2 or 3; each R^(3a) is independently selected from the groupconsisting of H, F, Cl, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃haloalkoxy, C₂₋₃ alkenyl and CN; R⁶, R⁷ and R⁸ are each independentlyselected from the group consisting of H, F, Cl, CN, CH₃, OCH₃, CH₂CH₃and CF₃; Z is a fused bicyclic heteroaryl ring, unsubstituted orsubstituted with one to three R^(c); each R^(a) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ alkylene-CO₂H, and C₁₋₆alkylene-SO₃H; each R^(b) is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ alkylene-CO₂H, and C₁₋₆ alkylene-SO₃H, each of whichis unsubstituted or substituted with one or two members independentlyselected from OH, SO₂NH₂, C(O)NH₂, C(O)NHOH, PO₃H₂, CO₂C₁₋₈ alkyl andCO₂H; and R^(a) and R^(b), when attached to the same nitrogen atom, areoptionally combined to form a 4- to 8-membered ring or spirocyclic ring,which is unsubstituted or substituted with halogen, OH, SO₂NH₂, C(O)NH₂,C(O)NHOH, PO₃H₂, CO₂C₁₋₈ alkyl or CO₂H; each R^(c) is independentlyselected from the group consisting of H, halogen, CN, C₁₋₆ haloalkyl,—Y¹, —X⁴—CO₂R^(a), —O—X⁴—CO₂R^(a), —X⁴—OR^(a), —X⁴—NR^(a)R^(b),—X⁴—C(O)NR^(a)R^(b), —O—X⁴—C(O)NR^(a)R^(b), —X⁴—SO₂R^(a),—X⁴—SO₂NR^(a)R^(b), —X⁴—SO₃R^(a), and —N(R_(a))—X⁴—CO₂R^(a), whereineach X⁴ is a bond or C₁₋₆ alkylene, and each Y¹ is selected from thegroup consisting of C₃₋₆ cycloalkyl and C₄₋₈ heterocyclyl; andoptionally two R^(c) on adjacent ring vertices are combined to form afused 5- or 6-membered heterocyclic ring.
 3. The compound of claim 1, ora pharmaceutically acceptable salt thereof having formula (Ia):


4. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein A is a 5- or 6-membered heteroaryl group which isunsubstituted or substituted with from one to three membersindependently selected from the group consisting of halogen, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, OH, and CN.
 5. The compound of claim 1, ora pharmaceutically acceptable salt thereof wherein A is a 6-memberedheteroaryl group which is unsubstituted or substituted with from one tothree members independently selected from the group consisting ofhalogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, OH, and CN.
 6. Thecompound of claim 1, or a pharmaceutically acceptable salt thereofhaving formula (Ib):


7. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein A is unsubstituted or substituted with one or twomembers independently selected from the group consisting of CF₃, OH, Et,CN, OCH₃ and F.
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof wherein A is a 6-membered heteroaryl groupselected from the group consisting of pyridine, pyrimidine, pyrazine and1,2,4-triazine, each of which is unsubstituted or substituted with oneor two members independently selected from the group consisting of CF₃,OH, Et, CN, OCH₃ and F.
 9. The compound of claim 1, or apharmaceutically acceptable salt thereof wherein Z is a fused bicyclicheteroaryl ring having a formula selected from the group consisting of:


10. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein —N(R^(2a))(R^(2b)) is selected from the group consistingof:


11. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein —N(R^(2a))(R^(2b)) is selected from the group consistingof:


12. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein —N(R^(2a))(R^(2b)) is selected from the group consistingof:


13. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein Y is selected from the group consisting of C₃₋₆cycloalkyl and C₄₋₈ heterocyclyl, each of which is unsubstituted orsubstituted with one to four substituents independently selected fromthe group consisting of oxo, OH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ hydroxyalkoxy, SO₂NH₂,C(O)NH₂, C(O)NHOH, PO₃H₂, CO₂C₁₋₈ alkyl, SO₃H and CO₂H.
 14. The compoundof claim 1, or a pharmaceutically acceptable salt thereof wherein A isselected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,oxazolyl, thiazolyl, and pyrazolyl, each of which is unsubstituted orsubstituted with one or two members independently selected from thegroup consisting of halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy,haloalkoxy, OH, and CN.
 15. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the compound is anoptically pure or enriched isomer.
 16. The compound of claim 1, whereinsaid compound is selected from the compounds in Table
 1. 17. Thecompound of claim 1, or a pharmaceutically acceptable salt thereofselected from the group consisting of:


18. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. 19.-20. (canceled)
 21. A method of modulating animmune response mediated by the PD-1 signaling pathway in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound of claim
 1. 22. A method of enhancing, stimulating,modulating and/or increasing the immune response in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of claim
 1. 23. A method of inhibitinggrowth, proliferation, or metastasis of cancer cells in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of any claim
 1. 24. A method of treatinga subject suffering from or susceptible to a disease or disordermediated by the PD-1 signaling pathway, comprising administering to thesubject a therapeutically effective amount of a compound of claim 1.25.-28. (canceled)
 29. A process for preparing a compound of formula(II),

the process comprising: (a) converting the compound having formula (2e1)to a compound having formula (2f1) with a borate reagent and a firstcatalyst;

(b) contacting a compound having formula (2f1) with a compound havingformula (2g1) and a second catalyst, under Suzuki-type conditions toproduce a compound having formula (2h1);

(c) reductively aminating the compound having formula (2h1) withHN(R^(2a))(R^(2b)) and a hydride reagent to provide the compound havingformula (II),

wherein in the above formulae (2e1), (2f1), (2g), (2h1), and (II), eachof Z, R^(2a), R^(2b), R³, R^(3a), subscript n, R⁴, R⁵, R⁶, R⁷, R⁸, havethe meanings provided in claim 1; each R′ is independently selected fromthe group consisting of H and C₁-C₆ alkyl; X is a member selected fromthe group consisting of Br and Cl; X′ is a member selected from thegroup consisting of I, Br and Cl; the ring bearing R^(s) is asix-membered nitrogen heteroaryl ring selected from the group consistingof pyridine, pyrimidine and pyrazine, and R^(s) is 0, 1, 2 or 3substituents independently selected from the group consisting ofhalogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, OH,and CN. 30.-31. (canceled)